Hla-b57 open conformers

Abstract

The invention relates to an open HLA-B57 conformer or an HLA-B57 FC fusion protein for use in the treatment or prevention of cancer. The open FC conformer comprises or consists of a first and a second monomer, each monomer comprising an HLA-B57 chain. The FC fusion protein further comprises a protein-stabilizing polypeptide sequence and, optionally, an amino acid linker. Other aspects of the invention provide combination medicines comprising the open HLA-B57 FC conformer and immune checkpoint inhibitors and / or checkpoint agonists. Furthermore, the invention relates to the use of the open HLA-B57 conformer as an immunomodulator, particularly in diseases where modulation of various components of immune cells (e.g., cytotoxic CD8+ T cells, Tregs) is a therapeutic strategy, for example, infectious diseases.

Description

1 / 58 “HLA-B57 OPEN CONFORMERS” Description

[0001] The present invention relates to the use of open HLA-B57 conformers, particularly for use in cancer prophylaxis or treatment, and for use as an immunomodulator.

[0002] Human leukocyte antigens (HLA) belong to the major histocompatibility complex (MHC) family of proteins. The HLA complex helps the immune system distinguish the body's own proteins from proteins produced by foreign invaders, such as viruses and bacteria. Humans have three main classical MHC class I genes, known as HLA-A, HLA-B, and HLA-C. The classical HLA genes have many possible variations, allowing each person's immune system to react to a wide range of foreign invaders. Some HLA genes have hundreds of identified versions (alleles), each of which is assigned a particular number (such as HLA-B57). Closely related alleles are categorized together; for example, at least 82 very similar alleles are subtypes of HLA-B57. These subtypes are designated as HLA-B*5701 to HLA-B*5782, and the closely related HLA-B*5801.

[0003] Classical MHC-I molecules (designated HLA-I in humans) are trimeric structures comprising a membrane-bound heavy chain with three extracellular domains (α1, α2, and α3) that non-covalently associate with 32-microglobulin (β2η) and a small peptide. HLA-I heavy chains can exist in a Petition 870250111294, dated 04 / 12 / 2025, p. 16 / 79 2 / 58 form not associated with p2-microglobulin or peptide. These forms are referred to as open conformers.

[0004] Like all other HLA molecules, the main function of HLA-B57 is to present cell-derived peptides to CD8+ cytotoxic T lymphocytes (CTLs) as part of the adaptive immune response. Under normal physiological conditions, HLA-B57 molecules form heterotrimeric complexes consisting of B57 heavy chains, p2-microglobulin, and peptides derived from autoproteins, viruses, or bacteria. In this respect, HLA-B57 resembles all other class I HLA alleles. However, HLA molecules can also be present in cells as free heavy chains without p2-microglobulin and peptide, and may be referred to as open conformers of HLA-B57 (Arosa et al. Open conformers: the hidden face of MHC-I molecules, Trends in Immunology 2007 Mar; 28(3):115-23).

[0005] Cancer is a group of diseases characterized by abnormal cells in the body that undergo uncontrolled destructive growth. Cancer cells can spread throughout the body and metastasize to form tumors; this growth pattern is called malignant. Cancer can be treated by surgery, chemotherapy, radiation therapy, hormone therapy, targeted therapy, and immunotherapy. The choice of therapy depends on the type of cancer, the stage of the cancer (how far it has spread), age, health status, and additional personal characteristics.

[0006] There is no single treatment for cancer, and patients usually receive a combination of therapies and palliative care. Petition 870250111294, dated 04 / 12 / 2025, page 17 / 79 3 / 58

[0007] Cancer immunotherapy refers to a diverse set of therapeutic strategies designed to induce the patient's own immune system to fight the tumor, and is based on the understanding that cancer progression, which involves the accumulation of various mutations, is monitored by the immune system. Immunotherapies stimulate the activities of specific cellular components of the immune system or neutralize signals produced by cancer cells that suppress immune responses. (Mahoney et al., Nat Rev Drug Discov. August 2015; 14(8):561-84).

[0008] Different types of immune cells are involved in the immune response against cancer. Within this set of white blood cells (immune context), the most notable cells are: T cells (cytotoxic CD8+ T cells, CD4+ helper T cells - Th1, Th2 and Th17 phenotypes), regulatory T cells (Tregs), macrophages (pro-inflammatory type M1 and pro-tumor type M2), myeloid-derived suppressor cells (MDSCs), natural killer cells (NK cells), and dendritic cells (DCs). These immune cells may be located in the center of the tumor, at the invasive margin, or in adjacent tertiary lymphoid structures. (Fridman et al., Nat. Rev. Cancer. 2012, April: 12, 298-306).

[0009] The density and composition of the immunological microenvironment are heterogeneous among patients and tumors. It is well established that, in general, tumor infiltration with M2 phenotype macrophages and myeloid-derived suppressor cells (MDSCs) promotes tumor progression, while infiltration of cytotoxic CD8+ T cells, cells of Petition 870250111294, dated 04 / 12 / 2025, page 18 / 79 4 / 58 Th1 phenotype and M1-type macrophages are frequently associated with a good clinical outcome and a good response to immunotherapy. The clinical impact of other lymphoid and myeloid cell populations is less consistent and appears to be dependent on the stage and type of tumor. The presence of Th17 and NK cells, and the absence / reduction of Treg cells in tumor infiltrates is correlated with a good outcome in some cancer indications (Giraldo et al., Current Opinion in Immunology 2014, 27:8-15). An overview of the balance between leukocyte infiltrates and clinical outcome is reviewed in Figure 1. (Becht et al. Current Opinion in Immunology. 2016, 39:17-13).

[0010] In general, modulating the immunological context of tumors by favoring the infiltration of M1-type macrophages, cytotoxic CD8 T cells, and cells, and / or reducing the infiltration of MDSCs and M2-type macrophages is a huge therapeutic avenue for treating cancer that is explored here with the use of B572-Fc proteins in various cancer indications. Terms and definitions

[0011] Amino acid sequences are given from the amino terminal to the carboxyl terminal. Uppercase letters for sequence positions refer to L-amino acids in the one-letter code (Stryer, Biochemistry, 3rd ed. page 21).

[0012] The term open conformer as used in this descriptive report refers to an isolated HLA heavy chain molecule not associated with 32-microglobulin, either as a monomer or as a dimer (homodimer or heterodimer). Certain embodiments of the open conformers disclosed herein are monomers or dimers of Petition 870250111294, dated 04 / 12 / 2025, page 19 / 79 5 / 58 fusion protein, in which the HLA heavy chain is covalently linked to a stabilizing polypeptide region, particularly a crystallizable fragment immunoglobulin domain.

[0013] In the context of this descriptive report, the terms sequence identity and percentage of sequence identity refer to the values ​​determined by comparing two aligned sequences. In the art, methods for aligning sequences for comparison are well known. Sequence alignment for comparison can be conducted using the local homology algorithm of Smith and Waterman, Adv. Appl. Math. 2:482 (1981), the global alignment algorithm of Needleman and Wunsch, J. Mol. Biol. 48:443 (1970), the search by a similarity method of Pearson and Lipman, Proc. Nat. Acad. Sci. 85:2444 (1988), or computerized implementations of these algorithms, including, without limitation: CLUSTAL, GAP, BESTFIT, BLAST, FASTA, and TFASTA. The software for performing BLAST analysis is publicly available, for example, through the National Center for Biotechnology Information (http: / / blast.ncbi.nlm.nih.gov / ).An example for comparing amino acid sequences is the BLASTP algorithm, which uses the following default definitions: Expected limit: 10; Word size: 3; Maximum match in a query range: 0; Matrix: BLOSUM62; Ga costs: Existence 11, Extension 1; Compositional adjustments: Conditional compositional classification matrix adjustment. An example for comparing nucleic acid sequences is the BLASTN algorithm, which uses the following default definitions: Expected limit: 10; Word size: 28; Maximum match in a range. Petition 870250111294, dated 04 / 12 / 2025, page 20 / 79 6 / 58 of consultations: 0; Match / No Match Ratings Correspondence: 1.-2; Gap Costs: Linear. Unless otherwise stated, sequence identity values ​​provided herein refer to the value obtained with the BLAST suite of programs (Altschul et al., J. Mol. Biol. 215:403 to 410 (1990)) which use the standard parameters identified above for protein and nucleic acid comparison, respectively.

[0014] In the context of this descriptive report, the term major histocompatibility complex (MHC) is used in its known meaning in the field of cell biology and biochemistry; it refers to a cell surface molecule that displays a specific moiety (peptide), also referred to as an epitope, of a protein. There are two main classes of MHC molecules: class I and class II.

[0015] MHC class I heavy chain molecules generally (i.e., when not in open conformer form) occur as an alpha chain linked to a non-MHC molecule p2-microglobulin unit. The alpha chain comprises, in the N-terminal to C-terminal direction, a signal peptide, three extracellular domains (α1 to 3, where α1 is at the N-terminal), a transmembrane region, and a C-terminal cytoplasmic tail. The peptide that is displayed or presented is held by the peptide-binding groove in the central region of the α1 / α2 domains.

[0016] In the context of this descriptive report, the term e2-microglobulin domain is used in its known meaning in the field of cell biology and Petition 870250111294, dated 04 / 12 / 2025, page 21 / 79 7 / 58 biochemistry; refers to a non-MHC molecule that is part of the MHC class I heterodimer molecule. In other words, it constitutes the β chain of the MHC class I heterodimer.

[0017] In the context of this descriptive report, the term human leukocyte antigen (HLA) is used in its known meaning in the field of cell biology and biochemistry; it refers to gene loci that encode human MHC class I proteins. The three main MHC class I genes in HLA are HLA-A, HLA-B, and HLA-C, and all these genes have a varying number of alleles; for example, HLA-B has 3590 known alleles. Closely related alleles are combined into subgroups of a certain allele. For example, the HLA-B57 allele has over 100 closely related alleles which are, according to the WHO Nomenclature Committee for HLA System Factors, labeled HLA-B*57:01:01 to HLA-B*57:82. The complete or partial sequence of all known HLA genes and their respective alleles are available to those skilled in the art in specialized databases such as IMGT / HLA (http: / / www.ebi.ac.uk / ipd / imqyhla / ) and are provided in Table 1 of this descriptive report.

[0018] In the context of this descriptive report, the term checkpoint inhibitor agent or checkpoint inhibitor antibody is intended to encompass an agent, particularly an antibody (or antibody-like molecule), that has the ability to interrupt the signaling cascade that leads to T cell inhibition after T cell activation as part of what is known in the art as the immunological checkpoint mechanism. Examples not Petition 870250111294, dated 04 / 12 / 2025, page 22 / 79 8 / 58 limiting factors of a checkpoint inhibitor agent or checkpoint inhibitor antibody include antibodies to CTLA-4 (Uniprot P16410), PD-1 (Uniprot Q15116), PD-L1 (Uniprot Q9NZQ7), B7H3 (CD276; Uniprot Q5ZPR3), Tim-3, Gal9, VISTA, Lag3.

[0019] In the context of this descriptive report, the term checkpoint agonist agent or checkpoint agonist antibody is intended to encompass an agent, particularly, without limitation, an antibody (or antibody-like molecule) that has the ability to undertake the signaling cascade that leads to T cell activation as part of what is known in the art as the immune checkpoint mechanism. Non-limiting examples of receptors known to stimulate T cell activation include CD122 and CD137 (4-1BB; Uniprot (Q07011). The term checkpoint agonist agent or checkpoint agonist antibody encompasses antibodies that are agonists to CD137 (4-1BB), CD134 (OX40), CD357 (GITR), CD278 (ICOS), CD27, and CD28.

[0020] In the context of this descriptive report, the term antibody is used in its known meaning in the art of cell biology and immunology; it refers to whole antibodies including, without limitation, immunoglobulin type G (IgG), type A (IgA), type D (IgD), type E (IgE) or type M (IgM), any antigen-binding fragment or single chains thereof and related or derived constructs. A whole antibody is a glycoprotein comprising at least two heavy (H) chains and two light (L) chains interconnected by disulfide bonds. Each heavy chain comprises Petition 870250111294, dated 04 / 12 / 2025, page 23 / 79 9 / 58 a variable heavy chain region (Vh) and a constant heavy chain region (Ch). The constant heavy chain region comprises three domains, Ch1, Ch2, and Ch3. Each light chain comprises a variable light chain region (abbreviated herein as Vl) and a constant light chain region (Cl). The constant light chain region comprises one domain, Cl. The variable regions of the light and heavy chains contain a binding domain that interacts with an antigen. The constant regions of antibodies can mediate the binding of immunoglobulin to host factors or tissues, including various cells of the immune system (e.g., effector cells) and the first component of the classical complement system.

[0021] The term antibody-like molecule in the context of this descriptive report refers to a molecule that has the ability to bind specifically to another molecule or target with high affinity / a Kd < 10E-8 mol / l. An antibody-like molecule binds to its target in a manner similar to the specific binding of an antibody. The term antibody-like molecule encompasses a repeat protein, such as an engineered ankyrin repeat protein (Molecular Partners, Zurich), a polypeptide derived from armadillo repeat proteins, a polypeptide derived from leucine-rich repeat proteins, and a polypeptide derived from tetratricopeptide repeat proteins.

[0022] The term antibody-like molecule additionally encompasses a polypeptide derived from protein A domains, a polypeptide derived from domains of Petition 870250111294, dated 04 / 12 / 2025, page 24 / 79 10 / 58 fibronectin FN3, a polypeptide derived from consensus fibronectin domains, a polypeptide derived from lipocalins, a polypeptide derived from zinc fingers, a polypeptide derived from Src homology domain 2 (SH2), a polypeptide derived from Src homology domain 3 (SH3), a polypeptide derived from PDZ domains, a polypeptide derived from gamma-crystalline, a polypeptide derived from ubiquitin, a polypeptide derived from a cysteine ​​knot polypeptide, and a polypeptide derived from knottin.

[0023] The term protein A domain-derived polypeptide refers to a molecule that is a derivative of protein A and has the ability to bind specifically to the Fc region and the Fab region of immunoglobulins.

[0024] The term armadillo repeat protein refers to a polypeptide comprising at least one armadillo repeat, wherein an armadillo repeat is characterized by a pair of alpha helices forming a hairpin structure.

[0025] In the context of this descriptive report, the term crystallizable fragment region (Fc) is used in its known meaning in the field of cell biology and immunology; it refers to a fraction of an antibody comprising two identical heavy chain fragments composed of a CH2 domain and a CH3 domain, covalently linked by disulfide bonds.

[0026] In the context of this descriptive report, the term dimer refers to a unit consisting of two subunits.

[0027] In the context of this descriptive report, the Petition 870250111294, dated 04 / 12 / 2025, page 25 / 79 11 / 58 The term homodimer refers to a dimer composed of two subunits that are either identical or are highly similar members of the same class of subunits. An example of a homodimer would be a dimer consisting of two independent subunits selected from the HLA-B57 allele list. In certain embodiments, homodimers consist of two identical HLA-B57 alleles.

[0028] In the context of this descriptive report, the term amino acid linker refers to a polypeptide of variable length that is used to connect two polypeptides to generate a single-chain polypeptide. Exemplary embodiments of linkers useful for the practice of the invention specified in this document are oligopeptide chains consisting of 1, 2, 3, 4, 5, 10, 20, 30, 40, or 50 amino acids. A non-limiting example of an amino acid linker is the polypeptide GGGGSGGGGSGGGGS (SEQ ID NO 109) which links an HLA-B57 polypeptide to an Fc domain.

[0029] The present invention provides HLA-B57 open conformers.

[0030] According to one aspect, the invention provides open HLA-B57 conformers for use as a medicament.

[0031] According to an alternative aspect, the invention provides open HLA-B57 conformers for use in cancer prevention or treatment, or as an immunomodulator.

[0032] According to another aspect of the invention, an isolated HLA-B57 open conformer protein is provided, particularly as a medicament, more Petition 870250111294, dated 04 / 12 / 2025, page 26 / 79 12 / 58 particularly for use in the treatment or prevention of cancer, or as an immunomodulator.

[0033] According to another aspect of the invention, an isolated HLA-B57 open conformer protein is provided as an immunomodulatory agent or for use as a negative modulator of regulatory T cells (Tregs), for use in human diseases in which Tregs impair the development of protective immunity, such as cancer and infectious diseases (von Boehmer et al. ibid.).

[0034] In certain embodiments, the open HLA-B57 conformer comprises two identical HLA-B57 polypeptide chains. In certain embodiments, the open HLA-B57 conformer comprises two different HLA-B57 polypeptide chains.

[0035] According to an alternative of this first aspect of the invention, an open HLA-B57 conformer is provided for use in the treatment or prevention of cancer, or for use as an immunomodulatory agent to treat infectious diseases, particularly for use in the prevention or therapy of human immunodeficiency virus (HIV), hepatitis A, B, C viruses (HAV, HBV, HCV respectively), influenza virus, Respiratory Syncytial Virus (RSV), measles virus, herpes virus and / or yellow fever virus. The open conformer according to this aspect is a fusion protein that exists as a dimer of two monomers, and each monomer independently of the other monomer comprises an HLA-B57 chain, and a polypeptide domain known to metabolically stabilize a polypeptide in vivo. An example of such a stabilizing domain is an Fc (crystallizable fragment) domain. Petition 870250111294, dated 04 / 12 / 2025, page 27 / 79 13 / 58 of an immunoglobulin, particularly the Fc polypeptide domain of a gamma immunoglobulin. The HLA-B57 chain and the stabilizing domain may optionally be joined by an amino acid linker. An open conformer fusion protein comprising the HLA-B57 chain and an Fc fragment of immunoglobulin is hereinafter referred to as the HLA-B57 Fc open conformer or B572-Fc in this document.

[0036] The presence of the Fc domain in the fusion protein facilitates increased solubility, stability, avidity, half-life and, from a technological point of view, cost-effective production and purification in mammalian systems (purification of protein A or G).

[0037] In certain embodiments, the HLA-B57 open conformer homodimer additionally comprises a peptide epitope fragment.

[0038] According to a second aspect of the invention, an open-conformer monomer of HLA-B57 (i.e., HLA-B57 not linked to a second HLA-B57 heavy chain polypeptide, and not linked by β2-microglobulin) is provided for use in the treatment or prevention of cancer, or for use as an immunomodulatory agent. In certain embodiments of this aspect, the HLA-B57 monomer further comprises a peptide epitope fragment.

[0039] This aspect can be summarized in the following items: Item 1: an isolated, essentially β2-microglobulin-free, simple HLA-B57 heavy chain polypeptide monomer for use as a medicament. Petition 870250111294, dated 04 / 12 / 2025, page 28 / 79 14 / 58 particularly for use in the treatment or prevention of cancer, or for use as an immunomodulatory agent. Item 2: the isolated single HLAB57 heavy chain polypeptide monomer for use in the treatment or prevention of cancer or as an immunomodulatory agent according to item 1, wherein the monomer additionally comprises a peptide epitope fragment. Item 3: the isolated simple HLA-B57 heavy chain polypeptide monomer for use in the treatment or prevention of cancer or as an immunomodulatory agent according to items 1 or 2, wherein the HLA-B57 chain consists only of the HLA-B57 alpha 1, 2 and 3 domains. Item 4: the isolated simple HLAB57 heavy chain polypeptide monomer for use in the treatment or prevention of cancer or as an immunomodulatory agent according to any of the preceding items, wherein the HLAB57 chain comprises the transmembrane domain and does not comprise the intracellular domain (cytoplasmic tail). Item 5: the isolated single HLAB57 heavy chain polypeptide monomer for use in the treatment or prevention of cancer or as an immunomodulatory agent according to any of the preceding items, wherein the HLAB57 chain has > 70%, > 80%, > 85%, > 90%, > 92%, > 93%, > 94%, > 95%, > 96%, > 97% or > 98%, or 100%, sequence identity compared with any of the sequences provided in Table 1. Item 6: a combination medicine comprising a. a single HLAB57 heavy chain polypeptide monomer isolated as specified in any of items 1 to 5, and Petition 870250111294, dated 04 / 12 / 2025, page 29 / 79 15 / 58 b. a checkpoint inhibitor, particularly a checkpoint inhibitor antibody, and / or a checkpoint agonist, particularly a checkpoint agonist antibody. Item 7: the combination medicinal product according to item 6, wherein said checkpoint inhibitor is selected from an inhibitor of CTLA4 interaction with CD80 or CD86, and an inhibitor of PD-1 interaction with its ligand PD-L1, particularly an antibody against any of CTLA4, CD80, CD86, PD-1, PD-L1, more particularly a monoclonal antibody against human CTLA4, PD-1, or PD-L1, and / or wherein said checkpoint agonist is selected from an agonist or ligand antibody to 4-1BB and / or 4-1BBL (CD137L, Uniprot P41273).

[0040] In certain embodiments of any of the aspects of the invention presented above, a peptide epitope fragment is non-covalently linked to the polypeptide on the antigen that presents the HLA-B57 peptide chain domain.

[0041] In certain embodiments of any of the aspects of the invention presented above, the HLA-B57 chain comprises only the extracellular HLA-B57 alpha 1, 2, and 3 domains. In these embodiments, the transmembrane and intracellular domains of the HLA-B57 chain are not included in the therapeutic polypeptide of the invention in order to allow its extracellular expression in recombinant cells. Those skilled in the art can easily identify the respective domains even in previously unknown HLA-B57 sequences by alignment. Petition 870250111294, dated 04 / 12 / 2025, page 30 / 79 16 / 58 of sequences paired with the annotated HLA-B57 sequences.

[0042] In certain embodiments of any of the aspects of the invention presented above, the HLA-B57 chain of the homodimer is selected from HLA-B*57:01 to HLA-B*57:82.

[0043] In certain embodiments of any of the aspects of the invention presented above, the HLA-B57 chain comprises only the HLA-B57 alpha 1, 2 and 3 domains, but not the transmembrane and intracellular domains of a sequence selected from Table 1.

[0044] In certain embodiments of any of the aspects of the invention presented above, the HLA-B57 chain has > %, > 80%, > 85%, > 90%, > 92%, > 93%, > 94%, > 95%, > 96%, >97%, or >98%, or 100% sequence identity compared to any of the sequences provided in Table 1.

[0045] In certain embodiments, the open conformer of HLA-B57 consists of two independently selected subunits of the HLA-B57 alleles above. In certain embodiments, homodimers consist of two identical HLA-B57 alleles.

[0046] In certain embodiments, the open conformer of HLA-B57 comprises an Fc domain. In certain particular embodiments, the Fc domain comprises constant regions of CH2 and CH3 heavy chains of immunoglobulin type G (IgG), type A (IgA), type D (IgD), type E (IgE), or type M (IgM).

[0047] In certain embodiments, the open conformer of HLA-B57 comprises an amino acid linker that binds a stabilizing domain, particularly an Fc domain, Petition 870250111294, dated 04 / 12 / 2025, p. 31 / 79 17 / 58 to the HLA polypeptide. In certain particular embodiments, the amino acid linker comprises 1 to 50 amino acids, particularly 5 to 40 amino acids, more particularly 10 to 30 amino acids, even more particularly 15 to 25 amino acids that link the HLA-B57 chain to the Fc domain as a single polypeptide chain.

[0048] According to a third aspect of the invention, a nucleic acid molecule is provided that encodes an HLA-B57 open conformer monomer, particularly an Fc open conformer monomer, according to the above aspects of the invention, for use in cancer treatment or therapy. In vivo expression of the nucleic acid molecule's open conformer will lead, after dimerization, to the fusion protein polypeptide of the invention. The concept of expressing pharmaceutically active nucleic acid polypeptides that encode them in the patient's body is well known and can confer significant benefits to the patient.

[0049] In certain embodiments, the nucleic acid molecule encodes an open-conformer monomer of HLA-B57, particularly an open-conformer Fc monomer comprising a peptide epitope fragment. In certain embodiments, the nucleic acid molecule encodes an open-conformer monomer of HLA-B57, particularly an open-conformer Fc monomer comprising only the extracellular domains of HLA-B57 alpha 1, 2 and 3. In certain embodiments, the nucleic acid molecule encodes an open-conformer monomer of HLA-B57, particularly an open-conformer Fc monomer comprising only the extracellular domains of HLA-B57. [Reference 870250111294, 04 / 12 / 2025, page 32 / 79] 18 / 58 B57 alpha 1, 2 and 3, and a peptide epitope fragment.

[0050] In certain embodiments, the nucleic acid molecule encodes an open-conformer monomer of HLA-B57, particularly an open-conformer monomer of Fc, which comprises an amino acid ligand and / or an Fc domain (crystallizable fragment), and is used in the treatment or therapy of cancer.

[0051] According to a fourth aspect of the invention, a recombinant expression vector is provided comprising the nucleic acid molecule according to the third aspect of the invention for use in the treatment or therapy of cancer.

[0052] In certain embodiments, the recombinant expression vector is a plasmid comprising a promoter that is operable in a mammalian cell, particularly a human cell. The promoter is operatively linked to the nucleic acid molecule of the invention.

[0053] According to another aspect of the invention, a virus comprising the nucleic acid molecule according to the third aspect of the invention is provided for use in the treatment or therapy of cancer. The nucleic acid molecule is under the control of a promoter sequence operable in a mammalian cell, particularly in a human cell. In certain embodiments, the virus is an adenovirus, adeno-associated virus, herpesvirus, or lentivirus.

[0054] According to yet another aspect of the invention, a genetically modified host cell is provided in vitro comprising the nucleic acid molecule according to the third aspect of the invention. Petition 870250111294, dated 04 / 12 / 2025, page 33 / 79 19 / 58

[0055] Another aspect of the invention provides the use of the HLA-B57 Fc open conformer homodimer or the fusion protein homodimer according to the first and second aspects of the invention in the manufacture of a medicament for the treatment or prevention of cancer.

[0056] According to yet another aspect, the invention provides a method of treating cancer comprising administering an open Fc HLA-B57 conformer according to the first and second aspects of the invention to a patient in need thereof.

[0057] According to another aspect of the invention, a combination medicinal product is provided, wherein the combination medicinal product comprises: - an open HLA-B57 conformer, particularly an open Fc HLA-B57 conformer, according to any of the above aspects or embodiments of the invention, and - a checkpoint inhibitor agent, particularly a checkpoint inhibitor antibody selected from an inhibitor of the interaction of cytotoxic T-lymphocyte-associated protein 4 (CTLA4; also known as CD152) with CD80 or CD86, an inhibitor of the interaction of programmed cell death protein 1 (PD-1; also known as CD279) with its ligand PD-L1, and a T-cell immunoglobulin ligand containing a mucin domain (TIM-3) - a checkpoint agonist agent, particularly a checkpoint agonist antibody selected to bind to and activate the tumor necrosis factor receptor. 4-1BB (also known as CD137 or TNFRSF9). Petition 870250111294, dated 04 / 12 / 2025, page 34 / 79 20 / 58

[0058] In certain modalities, the immune checkpoint inhibitor agent is an inhibitor of CTLA4 interaction with CD80 or CD86.

[0059] In certain embodiments, the immune checkpoint inhibitor agent is ipilimumab (Yervoy; CAS No. 477202-00-9).

[0060] In certain embodiments, the immune checkpoint inhibitor is an inhibitor of programmed cell death protein 1 (PD-1) interaction with its receptor PD-L1. In certain embodiments, the immune checkpoint inhibitor is selected from among the clinically available antibody drugs nivolumab (Bristol-Myers Squibb; CAS No. 946414-94-4), pembrolizumab (Merck Inc.; CAS No. 1374853-91-4), pidilizumab (CAS No. 1036730-42-3), atezolizumab (Roche AG; CAS No. 1380723-44-3), and avelumab (Merck KGaA; CAS No. 1537032-82-8).

[0061] In certain embodiments, the immune checkpoint agonist agent is utomilumab (PF-05082566), a fully human IgG2 monoclonal antibody against 4-1BB currently undergoing clinical trials.

[0062] In certain embodiments, the open conformer of HLA-B57, particularly the HLA-B57 Fc-open conformer, is supplied as a parenteral dosage form, specifically formulated for injection. In certain embodiments, the checkpoint inhibitor and / or checkpoint agonist are supplied as a parenteral dosage form, specifically formulated for injection. In certain embodiments, both the HLA-B57 open conformer and the checkpoint inhibitor and / or checkpoint agonist are... Petition 870250111294, dated 04 / 12 / 2025, page 35 / 79 21 / 58 present in the same form of administration.

[0063] In yet another aspect, the invention relates to a method for producing recombinant HLA heavy chain polypeptides. This method is summarized in the following items: Item A: a method for producing, by means of recombinant biotechnology methods, a human HLA heavy chain polypeptide, wherein said method comprises the following steps: a. Expression stage: i. an HLA-coding nucleic acid sequence encoding at least the alpha 1, alpha 2 and alpha 3 chains of an HLA heavy chain under the control of a promoter sequence operable in a cell, particularly a eukaryotic cell, more particularly a mammalian cell, and ii. a 32-microglobulin-coding nucleic acid sequence encoding human HLA beta 2 microglobulin (UniProt P617 69) under the control of a promoter sequence operable in said cell (the same cell as in item 1.a.) are co-expressed in a mammalian cell (“production cell line”); b. Purification step: the resulting HLA / ε2-microglobulin heavy chain complex is purified from the mammalian cell (the production cell line); c. Dissociation step: the purified HLA heavy chain and 32-microglobulin complex is dissociated under suitable conditions, and the HLA heavy chain polypeptides are separated from the ε2-microglobulin polypeptides; d. Refolding step: heavy chain polypeptides Petition 870250111294, dated 04 / 12 / 2025, page 36 / 79 22 / 58 of separated HLA molecules are incubated under conditions that lead to refolding (of their native tertiary protein structure found in physiologically active open-conformer HLA molecules). Item B: the method for producing a human HLA heavy chain polypeptide according to item A, wherein the HLA coding nucleic acid sequence comprises, from the N-terminal to the C-terminal of the encoded polypeptide, the alpha 1 chain, the alpha 2 chain, the alpha 3 chain and a stabilizing sequence. Item C: the method for producing a human HLA heavy chain polypeptide according to item B, wherein the stabilizing sequence is selected from bovine serum albumin and an immunoglobulin constant fragment (Fc), particularly an immunoglobulin G constant fragment, more particularly an IgG4 Fc. Item D: the method for producing a human HLA heavy chain polypeptide according to any of the preceding items, wherein the HLA-coding nucleic acid sequence and the 32-microglobulin-coding nucleic acid sequence are present in the same nucleic acid vector molecule (in particular, a DNA expression plasmid). Item E: the method for producing a human HLA heavy chain polypeptide according to any of the preceding items A to C, wherein the HLA-coding nucleic acid sequence and the 32-microglobulin-coding nucleic acid sequence are present in different nucleic acid vector molecules (in particular, different expression plasmids of Petition 870250111294, dated 04 / 12 / 2025, p. 37 / 79 23 / 58 DNA). Item F: the method of item E, wherein the nucleic acid vector comprising the HLA-coding nucleic acid sequence is present in an excess of approximately 1 to 5 times, particularly an excess of 1.5 to 5 times relative to the nucleic acid vector comprising the 32-microglobulin-coding nucleic acid sequence, particularly in an excess of approximately 3 times. Item G: the method of any of the preceding items, in which the HLA-coding nucleic acid sequence comprises an immunoglobulin Fc fragment as a stabilizing sequence and the purification step is effected by the absorption of recombinant HLA heavy chain polypeptides onto a protein A-bound surface. Item H: the method of any of the preceding items, in which the dissociation step is carried out by treatment under acidic conditions, particularly at a pH of approximately 2, and dialysis under reducing conditions. Item I: the method of any of the previous items, in which the doubling step is carried out by treatment under neutral conditions.

[0064] More specifically pointed out in the B57 open forming machines specified in this document, the method can be summarized in the following items: Item A': a method for producing, by means of recombinant biotechnology methods, a human HLA-B57 heavy chain polypeptide, wherein said method comprises the following steps: a. Expression stage: Petition 870250111294, dated 04 / 12 / 2025, page 38 / 79 24 / 58 i. a nucleic acid sequence encoding HLA-B57 that encodes at least the alpha 1, alpha 2 and alpha 3 chains of an HLA-B57 heavy chain under the control of a promoter sequence operable in a cell, particularly a eukaryotic cell, more particularly a mammalian cell, and ii. a p2-microglobulin-encoding nucleic acid sequence encoding human HLA beta 2 microglobulin (UniProt P617 69) under the control of a promoter sequence operable in said cell (the same cell as in item 1.a.) are co-expressed in a mammalian cell (“production cell line”); b. Purification step: the resulting HLA-B57 / p2-microglobulin heavy chain complex is purified from the mammalian cell (the production cell line); c. Dissociation step: the purified HLA-B57 / p2-microglobulin heavy chain complex is dissociated under suitable conditions and the HLA heavy chain polypeptides are separated from the e2-microglobulin polypeptides; d. Refolding step: the separated HLA-B57 heavy chain polypeptides are incubated under conditions that lead to refolding (of their native tertiary protein structure found in physiologically active HLA open conformer molecules). Item B': the method for producing a human HLA-B57 heavy chain polypeptide according to item A', wherein the nucleic acid sequence encoding HLA-B57 comprises, from the N-terminus to the C-terminus of the encoded polypeptide, the alpha 1 chain, the alpha 2 chain, the alpha 3 chain Petition 870250111294, dated 04 / 12 / 2025, page 39 / 79 25 / 58 and a stabilization sequence. Item C': the method for producing a human HLA-B57 heavy chain polypeptide according to item B', wherein the stabilizing sequence is selected from bovine serum albumin and an immunoglobulin constant fragment (Fc), particularly an immunoglobulin G constant fragment, more particularly an IgG4 Fc. Item D': the method for producing a human HLA-B57 heavy chain polypeptide according to any of the preceding items, wherein the HLA-coding nucleic acid sequence and the 32-microglobulin-coding nucleic acid sequence are present in the same nucleic acid vector molecule (in particular, a DNA expression plasmid). Item E': the method for producing a human HLA-B57 heavy chain polypeptide according to any of the preceding items A' to C, wherein the HLA-coding nucleic acid sequence and the 32-microglobulin-coding nucleic acid sequence are present in different nucleic acid vector molecules (in particular, different DNA expression plasmids). Item F': the method of item E', wherein the nucleic acid vector comprising the HLA-coding nucleic acid sequence is present in an excess of approximately 1 to 5 times, particularly an excess of 1.5 to 5 times relative to the nucleic acid vector comprising the 32-microglobulin-coding nucleic acid sequence, particularly in an excess of approximately 3 times. Petition 870250111294, dated 04 / 12 / 2025, page 40 / 79 26 / 58 Item G': the method of any of the preceding items, wherein the nucleic acid sequence encoding HLA-57 comprises an immunoglobulin Fc fragment as a stabilizing sequence and the purification step is effected by uptake of recombinant HLA heavy chain polypeptides onto a protein A-bound surface. Item H': the method of any of the preceding items, wherein the dissociation step is effected by treatment under acidic conditions, particularly at a pH of approximately 2, and dialysis under reducing conditions. Item I': the method of any of the preceding items, in which the doubling step is carried out by treatment under neutral conditions.

[0065] Whenever alternatives for unique separable features, such as a coding sequence or allele, are presented herein as “embodiments,” it should be understood that such alternatives may be freely combined to form distinct embodiments of the invention disclosed herein.

[0066] The invention is further illustrated by the following examples and figures, from which more embodiments and advantages can be established. These examples are intended to illustrate the invention, but do not limit its scope. Brief Description of the Figures

[0067] Figure 1 is a schematic representation showing three different classifications of tumors based on their immune cell infiltrates. Immunogenic tumors are characterized by abundant infiltration of cytotoxic T lymphocytes (CTLs), M1-type macrophages, and the presence of tertiary lymphoid structures. Petition 870250111294, dated 04 / 12 / 2025, page 41 / 79 27 / 58 (TLS) and low / moderate vascularization are associated with greater patient survival. Immunologically neglected tumors are characterized by a lack of infiltration by immune cells, low / moderate vascularization, and an intermediate prognosis. Finally, inflammatory tumors are characterized by abundant CTLs in the absence of SLT, conspicuous infiltration with M2 macrophages, severe vascularization, and an unfavorable prognosis (Becht et al. Current Opinion in Immunology. 2016, 39:17-13).

[0068] Figure 2 shows that B572-Fc blocks the conversion of mouse CD4+ T cells into iTregs. Dose-dependent incubation of B572-Fc with naive CD4+ T cell blocks blocks conversion into iTregs. A) B572-Fc blocks the expression of CD25 (Treg lineage marker) in a dose-dependent manner (^g / 200 pl) (C). B) B572-Fc blocks the expression of FoxP3 (Treg differentiation marker) in a dose-dependent manner (^g / 200 pl) (D). Control, isotype, TGFpβ and IL-2 supplemented medium and unsupplemented medium B57-p2m-Fc demonstrate the specific influence of B572-Fc on iTreg conversion.

[0069] Figure 3 shows that B572-Fc impairs murine Treg suppression in a dose-dependent manner. A) Histogram of CD8+ T cell and Treg proliferation showing B572-Fc blocking mouse Treg suppression and allowing CD8* T cell proliferation. Control B57-p2m-Fc isotype does not alter mouse Treg suppression function. B) Percentage of iTreg suppression of murine CD8+ T cells. Petition 870250111294, dated 04 / 12 / 2025, page 42 / 79 28 / 58 different concentrations of B572-Fc ^g / 200 μA).

[0070] Figure 4 shows that B572-Fc suppresses lymphoma T cells. A to C) Suppression assays to determine cell proliferation in the presence of (A) control isotype, (B) control B57-p2m-Fc and (C) B572-Fc. B572-Fc suppresses human (Jurkat) and mouse (EG.7) lymphoma cell lines in a dose-dependent manner (pg / 200 μL) compared to control cell lines.

[0071] Figure 5 shows the interaction of B572-Fc with different immunological regulatory receptors of leukocyte populations. A) KIR3DL1 (expressed on NK cells and T cell subsets); B) KIR3DL2 (expressed on NK cells and T cell subsets); C) KIR3DL3 (expressed on NK cells and T cell subsets); D) LILRB1 (expressed on NK cells, T cells, monocytes, and macrophages); E) LILRB2 (expressed mainly on macrophages and MDSCs); and F) PirB (murine homolog to LILRB2) by enzyme-linked immunosorbent assay (ELISA).

[0072] Figure 6 shows a schematic representation of B57-Fc and p2m DNA cassettes and the expression of B57-p2m-Fc molecules from CHO cells. A) HLA-B57 heavy chain alpha 1, 2, and 3 domains inserted into a human IgG4-Fc vector cassette; and human p2-microglobulin inserted into a separate vector cassette. B) Transfections in Chinese hamster ovary (CHO) cells are performed using the B57-Fc + p2m vector at a 1:1 ratio for extracellular production of the B57-p2m-Fc protein. Supernatants were collected and purified from B57-p2m-Fc using standard antibody purification protocols. Petition 870250111294, dated 04 / 12 / 2025, page 43 / 79 29 / 58 p2m is removed from the B57-p2m-Fc complex, and then the B57-Fc monomers are refolded to form B572-Fc homodimers.

[0073] Figure 7 shows that the combination of B572-Fc with PD-1 antibodies reduces tumor size in the murine syngeneic carcinoma model C38. A) Experimental point-time model of colon carcinoma cell (C38) injection and compound injection. B) Mean tumor volume mm3 of treated groups (n=6). C) Percentage of tumor inhibition of groups treated with B572-Fc and PD-1 compared to isotype. The experimental substance injection model was as follows: PBS Q3Dx7 vehicle, Q3Dx7 isotype (10 mg / kg); B572-Fc (10 mg / kg) Q3Dx7; PD-1 twice weekly x 2 (200 pg); and B572-Fc + PD-1 (Q3Dx7 and twice weekly x 2, respectively). Tumor volumes are expressed as mean ± SEM and analyzed by two-way ANOVA followed by Bonferroni post-hoc analysis, **p<0.01. Q = days between injections; Dx = number of injections, biwk = twice a week.

[0074] Figure 8 shows how the combination of B572-Fc with PD-1 antibodies reduces tumor size in the mouse model of pancreatic cancer (Pan02). A) Experimental point-in-time model of pancreatic cancer cell (Pan02) injection and compound injection. B) Mean tumor volume mm3 of groups treated (n=8) with B572Fc and / or PD-1. The experimental injection model was as follows: isotype (5 mg / Kg) twice a week x 3; B572-Fc (5 mg / kg) twice a week x 3; PD-1 (5 mg / kg) twice a week x 3; and B572-Fc + PD-1 (twice a week x 3). Tumor volumes are Petition 870250111294, dated 04 / 12 / 2025, page 44 / 79 30 / 58 expressed as mean ± SEM and analyzed by two-way ANOVA followed by Bonferroni post-hoc analysis, *p<0.05; **p<0.01; ****p<0.0001. biwk= twice a week.

[0075] Figure 9 shows that the combination of B572-Fc with PD-L1 antibodies reduces tumor size in the mouse model of pancreatic cancer (Pan02). A) Mean tumor volume mm3 of groups treated (n=8) with B572-Fc and / or PD-L1. B) Percentage of tumor inhibition of groups treated with B572-Fc, PD-1 and PD-L1 compared to isotype. The experimental injection model was as follows: isotype (5 mg / kg) twice a week x 3; B572-Fc (5 mg / kg) twice a week x 3; PD-L1 (5 mg / kg) twice a week x 3; and B572-Fc + PD-L1 (twice a week x 3). Tumor volumes are expressed as mean ± SEM and analyzed by two-way ANOVA followed by Bonferroni post-hoc analysis, *p<0.05; **p<0.01; ****p<0.0001. biwk= twice a week.

[0076] Figure 10 shows the immunological context analysis of leukocytes infiltrating tumors in mice with pancreatic cancer (Pan02) treated with B572-Fc and PD-1 by flow cytometry. Relevant leukocytes analyzed that infiltrate the tumor: A) NK cells; B) CD8 / Treg ratio; and C) Myeloid-Derived Suppressor Cells (MDSCs); Leukocyte numbers are expressed as mean ± SEM and analyzed by one-way ANOVA followed by Tukey post-hoc analysis, *p<0.05.

[0077] Figure 11 shows the immunological context analysis (continuation of Figure 10) of leukocytes infiltrating tumors in cancerous mice. Petition 870250111294, dated 04 / 12 / 2025, page 45 / 79 31 / 58 pancreatic (Pan02) tumors treated with B572-Fc and PD-1 by flow cytometry. Relevant leukocytes analyzed that infiltrate the tumor: A) Macrophages, and B) ratio between M1 / M2 macrophages. Leukocyte counts are expressed as mean ± SEM and analyzed by one-way ANOVA followed by Tukey's post-hoc test, *p<0.05; **p<0.01; ***p<0.001.

[0078] Figure 12 shows the immunological context analysis of leukocytes infiltrating tumors in mice with pancreatic cancer (Pan02) treated with B572-Fc and PD-L1 by flow cytometry. Relevant leukocytes analyzed that infiltrate the tumor: A) NK cells; B) CD8 / Treg ratio; and C) Myeloid-Derived Suppressor Cells (MDSCs). Leukocyte numbers are expressed as mean ± SEM and analyzed by one-way ANOVA followed by Tukey's post-hoc analysis, *p<0.05.

[0079] Figure 13 shows the immunological context analysis (continuation of Figure 12) of leukocytes infiltrating tumors in mice with pancreatic cancer (Pan02) treated with B572-Fc and PD-L1 by flow cytometry. Relevant leukocytes analyzed that infiltrate the tumor: A) Macrophages, and B) ratio between M1 / M2 macrophages. Leukocyte counts are expressed as mean ± SEM and analyzed by one-way ANOVA followed by Tukey's post-hoc test, *p<0.05; **p<0.01.

[0080] Figure 14 shows that the combination of B572-Fc with 4-1BB checkpoint agonist antibodies reduces tumor size in the mouse melanoma cancer model (B16F10). A) Experimental model of melanoma cancer cell injection time points (B16F10) and Petition 870250111294, dated 04 / 12 / 2025, page 46 / 79 32 / 58 compound injection. B) Mean tumor volume mm3 of groups treated (n=8) with B572-Fc and 4-1BB antibody. The experimental model of substance injection was as follows: isotype injections (5 mg / kg) twice a week 3; B572-Fc injections (5 mg / kg) twice a week 3; 4-1BB antibody injections (1 mg / kg) twice a week x 3; and B572-Fc + 4-1BB injections twice a week 3. Tumor volumes are expressed as mean ± SEM and analyzed by two-way ANOVA followed by Bonferroni post-hoc analysis, **p<0.01; ****p<0.0001. biwk= twice a week.

[0081] Figure 15 shows that the combination of B572-Fc with checkpoint agonist antibodies 4-1BB and combinations with antagonist antibodies PD-1 reduces tumor size in the mouse melanoma cancer model (B16F10) (continuation of the experiment in Figure 14). A) Mean tumor volume mm3 of groups treated (n=8) with B572-Fc, PD-1 and 4-1BB antibodies. B) Percentage of tumor inhibition of groups treated with B572-Fc, 4-1BB and PD-1 compared to isotype. The experimental injection pattern was as follows: isotype injections (5 mg / kg) twice a week 3; B572-Fc injections (5 mg / kg) twice a week 3; 4-1BB antibody injections (1 mg / kg) twice a week 3; PD-1 injections twice a week 3 (5 mg / kg); and injections of B572-Fc + 4-1BB twice a week 3, injections of B572-Fc + PD-1 twice a week 3, injections of PD-1 + 4-1BB twice a week 3, and injections of B572-Fc + 4-1BB + PD-1 twice a week 3.Tumor volumes are expressed as mean ± SEM. biwk = twice a week. Petition 870250111294, dated 04 / 12 / 2025, page 47 / 79 33 / 58

[0082] Figure 16 shows the immunological context analysis of leukocytes infiltrating tumors in mice with melanoma (B16F10) treated by flow cytometry. Relevant leukocytes analyzed that infiltrate the tumor: A) NK cells; B) CD8 / Treg ratio; and C) Cells Myeloid-Derived Suppressor Cells (MDSCs). Leukocyte counts are expressed as mean ± SEM and analyzed by one-way ANOVA followed by Tukey's post-hoc analysis, *p<0.05; **p<0.01; ***p<0.001; ****p<0.0001.

[0083] Figure 17 shows the immunological context analysis (continuation of Figure 16) of leukocytes infiltrating tumors in mice with melanoma (B16F10) treated by flow cytometry. Relevant leukocytes analyzed that infiltrate the tumor: A) Macrophages; and B) M1 / M2 Macrophage ratio. Leukocyte numbers are expressed as mean ± SEM and analyzed by one-way ANOVA followed by Tukey's post-hoc analysis, *p<0.05; **p<0.01; ***p<0.001. Examples

[0084] The inventors surprisingly found that open HLA-B57 conformers interact with different immune-modulating surface receptors present on NK cells, T cells, myeloid-derived cells (macrophages and MDSCs), and regulate the differentiation and suppressive function of Tregs in vitro.

[0085] The inventors surprisingly found that open HLA-B57 conformers, particularly when present as fusion proteins comprising an Fc immunoglobulin fragment, could be useful in cancer therapy. HLA-B57-Fc molecules can be Petition 870250111294, dated 04 / 12 / 2025, page 48 / 79 34 / 58 used alone or in combination with other therapeutic agents against cancer.

[0086] Additionally, they observed an innovative in vivo mode of action with B572-Fc injections as monotherapy or in combination with checkpoint inhibitors or antibody agonists. B572-Fc therapy alone or in combination can regulate the infiltration of various leukocyte sets into tumors as determined by the increased M1 / M2 cell ratio, increased NK cell infiltration, increased CD8+ / Treg T cell ratio, and reduced MDSC infiltration. Overall, the mode of action of B572-Fc alone or in combination with antagonistic / agonistic antibodies is of undeniable relevance in cancer treatment and correlates with the current clinical need in cancer immunotherapy.

[0087] HLA-B57 open Fc conformers can be used as a therapeutic agent to target diseases where immunomodulation is a therapeutic approach, as is the case in cancer and infectious diseases. In vitro tests

[0088] The B572-Fc molecule has the ability to modulate immune responses by blocking iTreg differentiation and negatively influencing Treg suppression (Figures 2 and 3) B572-Fc blocks the conversion of murine CD4+ T cells into iTregs.

[0089] The influence of HLA molecules on T cells CD4+naive iTreg conversion was analyzed in a dose-dependent manner (g / ml) with B572-Fc, B57-p2m-Fc, isotype Petition 870250111294, dated 04 / 12 / 2025, page 49 / 79 35 / 58 and PBS incubated with naive CD4+ T cells under optimal culture conditions for iTreg conversion. B572-Fc demonstrated downmodulation of CD25 induction (Figures 2A, C) and FoxP3 induction (Figures 2B, D). B5 72-Fc impairs the suppression of mouse CD8+ T cells by Tregs.

[0090] The suppressive function of murine Tregs using violet-labeled naive CD8+ T cells as responsive cells was determined (Figure 3). Tregs were co-cultured with B572-Fc and B57-p2m-Fc controls, and isotype antibody, and CD8+ T cell proliferation was measured after 96 h. CD8+ T cells alone showed strong proliferation and, as expected, Treg cells suppressed CD8+ T cell proliferation when incubated with controls (B57-p2m-Fc, and isotype). Surprisingly, the suppressive function of Tregs was greatly impaired in the presence of B572-Fc indicated by strong CD8+ T cell proliferation (Figure 3A). The effect of B572-Fc was dose-dependent (Figure 3B). B572-Fc impairs leukemia T cell proliferation.

[0091] The effect of the proliferation effect of B572-Fc on different cancer cell lines was determined (Figure 4). The results demonstrated that B572-Fc modulates the proliferation of lymphoma T cell lines, compared to the control counterpart B57-p2m-Fc or IgG4 isotype, indicating its potential application in the treatment of lymphoma as a targeted therapy. B572-Fc binds to immunomodulatory receptors expressed on various types of leukocytes. It was determined whether B572-Fc interacts with receptors. Petition 870250111294, dated 04 / 12 / 2025, page 50 / 79 36 / 58 specific immunological regulatory receptors were identified using enzyme-linked immunosorbent assay (ELISA). The results demonstrated that B5 72-Fc interacts with KIR3DL1, KIR3DL2, KIR3DL3, LILRB1, LILRB2, and Pirb receptors differently from its control counterpart B57-e2m-Fc (Figures 5A to D). Furthermore, B272-Fc and B27-e2m-Fc were also compared to demonstrate whether similar HLA open conformer molecules interact with the same receptors but with different affinities. Production of B57 open conformers as a human Fc fusion protein in CHO cells

[0092] A valid strategy, from a therapeutic point of view, is to produce HLA-B57 open conformer molecules in a stable format (Fc fusion), to increase solubility, stability, avidity, half-life, and from a technological point of view, cost-effective production and purification in mammalian systems. The B57-p2m-Fc complex was successfully produced by inserting the alpha 1, 2 and 3 domains of HLA-B57 into a vector cassette of Human IgG4-Fc (Figure 6A), along with a human p2m vector, necessary for the extracellular production of the B57-p2m-Fc protein (Figure 6A, B). Transfections were performed in Chinese hamster ovary (CHO) cells using the B57-Fc vector + p2m vector at a 1:1 ratio. The supernatants were collected and purified by B57-p2mFc using standard antibody purification protocols (Recombinant Protein Purification Handbook, principles and methods. 2009. GE Healthcare, 18-1142 a 75) (Figure 6B). The separation of p2m from free B57-Fc heavy chains was performed using conditions Petition 870250111294, dated 04 / 12 / 2025, page 51 / 79 37 / 58 denaturants by SEC or dialysis methods. B572-Fc refolding was evaluated using the refolding buffer dilution method and analyzed by western blot (data not shown). Preclinical combination therapy trials of B572-Fc with PD-1, PD-L1 and 4-1BB antibodies in various mouse models of syngeneic colon cancer.

[0093] The in vivo proof-of-concept study of B572-Fc as an immunomodulatory therapeutic molecule was demonstrated in a syngeneic mouse model of colon carcinoma (C38), pancreatic cancer (Pan02) and murine melanoma (B16F10) as monotherapy and in combination antibodies with PD-1, PD-L1 or 4-1BB.

[0094] For the colon carcinoma model, following established protocols, C38 fragment tumors were subcutaneously injected into the flank of syngeneic mice. Once the tumor reached ~80 mm3 (between 1 and 2 weeks after tumor transplantation), mice were statistically distributed according to their tumor volume. B572-Fc was injected intraperitoneally seven times every 3 days (Q3Dx7), and PD-1 was injected 4 times biwk (twice a week x 2) (Figure 7A).

[0095] In colon cancer (C38), data demonstrated that the combination of B572-Fc with PD-1 antibodies significantly reduces tumors (Figure 7B). The combination therapy of B572-Fc + PD-1 versus isotype control antibody surprisingly reduced tumor volume (333 mm3 vs 2120 mm3, respectively, p<0.01). Additionally, the combination therapy of B572-Fc + PD-1 versus PD-1 monotherapy Petition 870250111294, dated 04 / 12 / 2025, page 52 / 79 38 / 58 also showed a significant reduction in tumor size (333 mm3 vs 1423 mm3, respectively, p<0.01) (Figure 7B). Monotherapy with B572-Fc or monotherapy with PD-1 showed no differences vs. isotype control at the end of the experiment; however, on day 24, mice treated with B572-Fc were significantly different from isotype (384 mm3 vs 652 mm3, p<0.05), as well as from PD-1 vs isotype (151 mm3 vs 652 mm3, p<0.01) (Figure 7B), indicating that B572-Fc monotherapy also has immunomodulatory effects on tumor progression in colon cancer mice.

[0096] For the pancreas (Pan02) and melanoma (B16F10) mouse models, following established protocols, cells were injected at 1 x105 into the right flank of syngeneic mice, respectively. Once the tumor reached ~80 mm3 (between 1 and 2 weeks after cell injection), mice were statistically distributed according to their tumor volume (Figures 8A, 14A).

[0097] In the pancreas (Pan02), data demonstrated that B572-Fc monotherapy and combination with PD-1 antibodies can significantly reduce tumors (Figures 8B, 9B). Combination therapy of B572-Fc + PD-1 vs. isotype control antibody demonstrated a surprisingly significant reduction in tumor volume (216 mm3 vs. 799 mm3, respectively, p<0.0001) (Figure 8B). Additionally, combination therapy of B572-Fc + PD-1 vs. PD-1 monotherapy also showed a significant reduction in tumor size (216 mm3 vs. 445 mm3, respectively, p<0.01) (Figure 8B). B572-Fc monotherapy was significantly different. Petition 870250111294, dated 04 / 12 / 2025, page 53 / 79 39 / 58 compared with the isotype (545 mm3 vs. 799 mm3, respectively, p<0.05). PD-1 monotherapy was significantly different compared with the isotype (445 mm3 vs. 799 mm3, respectively, p<0.0001) (Figure 8B).

[0098] In the pancreas (Pan02), the study of B572-Fc in combination with PD-L1 antibodies significantly reduced tumors (Figures 9A and B). The combination therapy of B572-Fc + PD-L1 vs. isotype showed a significant reduction in tumor size (397 mm3 vs. 799 mm3, respectively, p<0.0001) (Figure 9A). PD-L1 monotherapy was significantly different compared to the isotype (531 mm3 vs. 799 mm3, respectively, p<0.01) (Figure 9A).

[0099] The pancreatic tumor immunological context mouse (Pan02) demonstrated the influence of B572-Fc therapy towards various tumor infiltration leukocyte clusters (Figures 10 to 13). B572-Fc monotherapy increased NK cell infiltration when compared with the control isotype (p<0.05) (Figure 10A), and significantly modified the M1 / M2 macrophage cell ratio (p<0.05) by favoring the presence of M1-type macrophages within the tumor (Figure 11B).Combination therapy with B572-Fc and PD-1 significantly reduced MDSC infiltration in the tumor compared to PD-1 monotherapy (p<0.05) (Figure 10C), reduced macrophage infiltration (Figure 11A) (p<0.05), and significantly modified the M1 / M2 macrophage ratio compared to PD-1 isotype and monotherapy (Figure 11B) (p<0.001). Combination therapy of... B572-Fc with PD-L1 (Figures 12 and 13) modified Petition 870250111294, dated 04 / 12 / 2025, page 54 / 79 40 / 58 significantly increased the cell ratio between M1 / M2 macrophages compared to the isotype (p<0.01) and PD-L1 (p<0.05) (Figure 13E).

[0100] In melanoma (B16F10), data have shown that B572-Fc in combination with 4-1BB agonist antibodies can significantly reduce tumors (Figures 14 and 15). The B572-Fc + 4-1BB combination therapy versus isotype control antibody showed a markedly significant difference in tumor volume reduction (756 mm3 versus 1,424 mm3, respectively, p<0.0001) (Figure 14B). Additionally, the B572-Fc + 4-1BB combination versus 4-1BB monotherapy also showed a significant reduction in tumor size (756 mm3 versus 1199 mm3, respectively, p<0.01) (Figure 14B). 4-1BB monotherapy was not significantly different compared to the isotype (1199 mm3 versus 1424 mm3, respectively). PD-1 monotherapy and combination therapy did not show significance between groups (Figure 15A). However, triple combination therapy (B572-Fc + 4-1BB + PD-1) showed a large significant difference compared to the isotype (p<0.0001), but was not better than the B572-Fc + 4-1BB combination (Figures 15A to B).

[0101] The tumor immunological context of animals treated with melanoma (B16F10) demonstrated the influence of B572—Fc therapy with various sets of tumor-infiltrating leukocytes (Figures 16 and 17). Monotherapy of B572-Fc significantly reduced the presence of MDSCs within the tumor compared to the isotype (p<0.05) (Figure 16C). Combination therapy with B572-Fc and 4-1BB antibodies significantly modified the presence Petition 870250111294, dated 04 / 12 / 2025, page 55 / 79 41 / 58 of CD8+ T cells versus Treg cells, as measured by the CD8+ / Treg T cell ratio (p<0.05) (Figure 16B), significantly reduced the presence of MDSCs within the tumor (p<0.05) (Figure 16C) and significantly modified the M1 / M2 macrophage ratio compared to isotype and 4-1BB monotherapy (p<0.05) (Figure 17B). Triple combination therapy of B572-Fc with 4-1BB and PD-1 antibodies significantly induced NK cell infiltration into the tumor (p<0.05) (Figure 16A), surprisingly modified the CD8+ / Treg T cell ratio compared to isotype (158% versus 23%, respectively, p<0.0001) and also compared to all other groups (Figure 16B). Furthermore, it significantly reduced the presence of MDSCs within the tumor (p<0.001) (Figure 16C) and significantly modified the M1 / M2 macrophage ratio compared to all other groups (Figure 17B). Conclusion

[0102] Proof of principle for the use of molecules The effectiveness of B572-Fc in combating cancer has been demonstrated using preclinical syngeneic mouse models of colon, pancreas, and melanoma. The present data demonstrate the therapeutic potential of B572-Fc as monotherapy and / or combination therapy with checkpoint inhibitors and / or checkpoint agonists, such as PD-1, PD-L1, or 4-1BB antibodies.

[0103] The mode of action of B572-Fc was also evaluated in vivo in mouse models of pancreas and melanoma, establishing tumor leukocyte infiltration. B572-Fc therapy can regulate the infiltration of various Petition 870250111294, dated 04 / 12 / 2025, pp. 56 / 79 42 / 58 leukocyte clusters in mouse tumors, as determined by the increased M1 / M2 macrophage cell ratio, reduced MDSC infiltration, increased CD8+ / Treg T cell infiltration ratio, and increased NK cell infiltration. In general, the mode of action of B572-Fc alone or in a combinational approach with antagonistic / agonistic antibodies is of undeniable relevance in cancer treatment and correlates with the current clinical need in cancer immunotherapy.

[0104] B572-Fc emerges as an innovative class of immunomodulatory drug. In vitro and in vivo data points to a mechanism were B572-Fc molecules acting as a binding mechanism for the activation of antitumor immunity. Without wishing to be confined to theory, the inventors speculate that the interaction of open HLA-B57 conformers that bind to various immunomodulatory receptors present on myeloid cells (Macrophages, MDSCs), T cells and NK cells participates synergistically and exacerbates the immune response. Materials and methods Cell Lines and Animals

[0105] In vivo experiments were conducted in C57BI / 6 mice using the C38 mouse colon carcinoma cell line, the Pan02 pancreatic ductal adenocarcinoma mouse cell line; and the B16F10 melanoma mouse cell line.

[0106] Cell lines from in vitro experiment: EG.7, mouse T-cell lymphoma; Jurkat, human T-cell lymphoma; L428, human Hodgkin lymphoma; L540, Petition 870250111294, dated 04 / 12 / 2025, pp. 57 / 79 43 / 58 human Hodgkin lymphoma; L1236, human Hodgkin lymphoma; Daudi, B-cell lymphoma; IMR-5, neuroblastoma; SK-N-AS, neuroblastoma; and M130428, Melanoma. In vivo treatments

[0107] C38 tumor fragments were injected subcutaneously into the right flanks of syngeneic female C57BL / 6 mice at week 6. Pan02 and B16F10 cell lines were injected at 1x10⁵ into the right flank of syngeneic mice at week 6. Once the tumor reached ±80 mm³ in the colon (C38), pancreas (Pan02), and melanoma (B16F10), the animals were sorted according to their individual tumor volume sizes and divided into groups that did not exhibit any statistical difference between them. Tumor diameters were measured using a caliper, and volume was calculated according to the formula, D / 2xd², where D and d are the longest and shortest tumor diameters in mm, respectively.

[0108] The experimental design of point-in-time cell injection and substance injection was established as follows for colon (C38), vehicle (200 μL PBS); isotype (10 mg / kg) Q3Dx7; B572—Fc (10 mg / kg); PD-1 twice weekly x 2 (200 pg); B572—Fc + PD-1 (Q3Dx7 and twice a week x 2, respectively), B272—Fc + PD-1 (Q3Dx7 and twice a week x 2, respectively). For the pancreas (Pan02), the experimental injection design was as follows: isotype (5 mg / kg) twice a week x 3; B572Fc (5 mg / kg) twice a week x 3; PD-1 twice a week x 3 (5 mg / kg); PD-L1 twice a week x 3 (5 mg / kg); B572-Fc + PD-1 (twice a week x 3) and B572Petition 870250111294, dated 04 / 12 / 2025, page 58 / 79 44 / 58 For melanoma (B16F10), the experimental injection design was as follows: 3 isotype injections (5 mg / kg) twice a week; 3 B572-Fc injections (5 mg / kg) twice a week; 3 4-1BB antibody injections (1 mg / kg) twice a week; 3 PD-1 injections twice a week (5 mg / kg); 3 B572-Fc + 4-1BB injections twice a week, 3 B572-Fc + PD-1 injections twice a week, 3 PD-1 + 4-1BB injections twice a week, and B572-Fc + 4-1BB + PD-1 injections twice a week.

[0109] Tumor sample preparation for flow cytometry was performed using protocols described by eBioscience (https: / / www.ebioscience.com / media / pdf / best-protocols / cellpreparation-for-flow-cytometry.pdf, accessed February 21, 2017). Antibodies

[0110] Mouse leukocyte populations for in vitro tests were stained with: CD3 (PE-Cy7eBioscience), CD4 (FITC-BD Bioscience), FoxP3+ (fluorine 450eBioscience), CD45 (PerCP-eBioscience), CD3 (PEeBioscience), NK1.1 (BV421-eBioscience), CD11b (FITCeBioscience), CD11c (FITC-eBioscience), CD25 (PE-Cy7Biolegend).

[0111] mAb of HC10 (IgG2a) that binds to free p2m heavy chains of HLA-B and -C alleles and consequently to B572, was a gift from Dr. Hidde Ploegh (MIT, MA).

[0112] Flow cytometry antibodies from tumor samples were stained with: CD45 (FITC; clone 30-F11; Biolegend), CD3 (PerCP / Cy5.5; clone 17A2; Biolegend), CD4 Petition 870250111294, dated 04 / 12 / 2025, pp. 59 / 79 45 / 58 (BV510; clone GK1.5; Biolegend), CD8 (APC-H7; clone 53-6.7; BD), FoxP3 (PE; clone FJK-16S; eBioscence), CD11b (BV650; clone M1 / 70; Biolegend), F4 / 80 (PE / Cy7; clone BM8; Biolegend), Gr-1 (APC-R700; clone RB6-8C5; BD), NK1.1 (BV605; clone PK136; Biolegend), CD206 (APC; clone C068C2; Biolegend), CD86 (BV421; clone GL-1; Biolegend), L / D stain (BUV395; Invitrogen).

[0113] The RMP1-14 clone of PD-1 checkpoint inhibitor anti-mouse antibody was obtained from BioXCell. The 10F.9G2 clone of PD-L1 checkpoint inhibitor anti-mouse antibody was obtained from Bio X Cell. The 3H3 clone of 4-1BB agonist anti-mouse antibody was obtained from Bio X Cell. Leukocyte flow cytometry

[0114] Flow cytometry analysis was performed using a FACScanto II (BD Bioscience) and data were analyzed using FlowJo version 7.6.4. Tregs Generation

[0115] To induce Foxp3 expression in murine CD4+ T cells, spleen cells from C57BL / 6 splenocytes were harvested and purified (Naive Mouse CD4+ T Cell Isolation Kit - Easy Sep) to obtain CD4+ T cells. The cells were then cultured at 96 ha 105 cells / 200 μL / well in 96-well plates with 5 μg / ml of coated anti-CD3mAb (eBioscience), 2 μg / ml of soluble anti-CD28 mAb (Biolegend), 10 μg / ml of TGF-β1 (R&D systems) and 100 IU / ml of IL-2 (R&D systems). iTreg conversion in the presence of B5 72-Fc

[0116] Murine naive CD4+ T cells under optimal culture conditions for iTreg conversion were Petition 870250111294, dated 04 / 12 / 2025, pp. 60 / 79 46 / 58 were incubated in the presence of different dose concentrations (pg / 200 pl) of B572-Fc, B57-p2m-Fc, B27-p2m-Fc, IgG4 isotype, and PBS for 72 h. iTreg conversion was measured by flow cytometry. Suppression test

[0117] Effector CD4+ or CD8+ T cells were purified mouse or human PBMCs (Naive Mouse CD4+ T Cell Isolation Kit - Easy Sep; Dynabeads® FlowComp™ Mouse CD8-life technologies; Dynabeads® CD8 human-Life Technologies) and labeled with a 10 μM cell trace violet proliferation stain (Molecular Probes). Tregs (2.5 x 10⁴) and effector T cells (2.5 x 10⁴) were cultured in 96-well U-bottom plates with coated CD3 antibody (eBioscience) (3 pg / ml) and soluble CD28 antibody (eBioscience) (1 pg / ml) for 96 h. Effector T cell proliferation was measured using a FACScanto II and data were analyzed using FlowJo proliferation analysis software version 7.6.4. Proliferation assay

[0118] Cells were plated in round well plates at a density of 5 x 10⁵ cells / well following the addition of drugs at different concentrations (10, 5, and 2 pg / well) for 1 day. The XTT proliferation assay was performed according to the instructions in the manual (Cell Proliferation Kit II, Roche). Results were obtained by measuring well absorbance at 450 nm using a microtiter plate reader. ELISA assays

[0119] Competition ELISA tests were performed using 96-cavity Maxisorp plates (Nunc, Switzerland) Petition 870250111294, dated 04 / 12 / 2025, pp. 61 / 79 47 / 58 cells were coated with 10 μg / ml of selected recombinant leukocyte receptors (human KIR3DL1, human KIR3DL2, human KIR3DL3, human LILRB1, human LILRB2, and mouse Pirb). The receptors were incubated by NO at 4 °C, blocked with 5% milk powder PBS for 2 h. B572-Fc, B57-p2m-Fc, B272-Fc, B27-p2m-Fc, and IgG4 isotypes were added at 2 μg / ml for 2 h at room temperature. HRP-conjugated antibodies against human Fc were used as detectors. Production, purification and refolding of B572-Fc

[0120] Recombinant production of B57-p2m-Fc was achieved by inserting the alpha 1, 2, and 3 domains of HLA-B57 into a human IgG4-Fc vector, and human 32-microglobulin (β2η) into a separate vector. Recombinant B57-p2m-Fc production was performed by co-transfection of B57Fc vector and p2m vector into Chinese hamster ovary (CHO) cells. B57-p2m-Fc production was outsourced to Evitria AG.

[0121] The purification of B57-p2m-Fc was performed using conventional antibody purification protocols. The production of B572-Fc was carried out with the addition of a denaturation step to remove p2m from the B57-p2m-Fc complex.

[0122] Briefly, the B57-p2m-Fc capture step was performed after passing supernatants (5 ml / min) through G protein columns (Amersham Pharmacia). Intermediate purification steps were performed by eluting B57-p2m-Fc from the G protein columns using elution buffer (100 mM glycine, pH 2.0), and recovering fractions in 8M urea, 100 mM Tris-HCl, and pH 8.0. The first Petition 870250111294, dated 04 / 12 / 2025, pp. 62 / 79 Step 48 / 58 of the polishing process involved separating the B57Fc monomer fractions from p2m by size exclusion chromatography (SEC) using grade Superdex 200 prep or Sefacril S-100 HR (GE Lifescience) with an AKTA system (GE Lifescience), or by dialysis with 30 kDa or 50 kDa pore size membranes (Millipore). The B57-Fc monomers recovered from both protocols were refolded by the dilution method after pulsing the B57-Fc monomers 3 times at 8-hour intervals in 100 times the volume of refolding buffer (50 mM Tris-HCl, pH 8.5, 500 mM L-Arginine, 1 mM EDTA, 0.15 mM NaCl, 1% sucrose). 0.01% Tween-20). The second polishing step by SEC was performed to remove additional impurities and to buffer newly recovered fractions of B572-Fc molecules in dilution buffer (PBS, 1% sucrose and 0.01% Tween-20). The purified solutions of B572-Fc were filter-sterilized using 0.2 µm membranes (Millipore).

[0123] B57-p2m-Fc fractional and B572-Fc complexes were analyzed by SDS-polyacrylamide gel electrophoresis (SDS-PAGE) and subjected to western blotting using HC10 antibodies (specific for HLA-free heavy chains). Western blots of p2m were performed with and without denaturation conditions (10 mM DTT) (data not shown). Complete and partial sequences of HLA-B57 alleles

[0124] The functional domains of the full-length N-terminal to C-terminal HLA-B57 alpha chain are: signal peptide, alpha 1, alpha 2, alpha 3, transmembrane domain and cytoplasmic tail. Petition 870250111294, dated 04 / 12 / 2025, pp. 63 / 79 49 / 58 Table 1: HLA-B57 Alleles

[0125] Sequence identification (comprimento em aa) Sequence of amino acids B*57:01:01 MRVTAPRTVLLLLWGAVALTETWAGSHSMRYFYTAMSRPGRGEPRFIAVGYVDDTQ HLA00381 FVRFDSDAASPRMAPRAPWIEQEGPEYWDGETRNMKASAQTYRENLRIALRYYNQS (362aa) EAGSHIIQVMYGCDVGPDGRLLRGHDQSAYDGKDYIALNEDLSSWTAADTAAQITQ RKWEAARVAEQLRAYLEGLCVEWLRRYLENGKETLQRADPPKTHVTHHPISDHEAT LRCWALGFYPAEITLTWQRDGEDQTQDTELVETRPAGDRTFQKWAAVVVPSGEEQR HLA01520 EYWDGETRNMKASAQTYRENLRIALRYYNQSEAGSHIIQVMYGCDVGPDGRLLRGH (181aa) DQSAYDGKDYIALNEDLSSWTAADTAAQITQRKWEAARVAEQLRAYLEGLCVEWLR RYLENGKETLQRA (SEQ ID 002) B*57:01:03 SHSMRYFYTAMSRPGRGEPRFIAVGYVDDTQFVRFDSDAASPRMAPRAPWIEQEGP HLA02259 EYWDGETRNMKASAQTYRENLRIALRYYNQSEAGSHIIQVMYGCDVGPDGRLLRGH (181aa) DQSAYDGKDYIALNEDLSSWTAADTAAQITQRKWEAARVAEQLRAYLEGLCVEWLR RYLENGKETLQRA (SEQ ID 003) B*57:01:04SHSMRYFYTAMSRPGRGEPRFIAVGYVDDTQFVRFDSDAASPRMAPRAPWIEQEGP HLA03969 EYWDGETRNMKASAQTYRENLRIALRYYNQSEAGSHIIQVMYGCDVGPDGRLLRGH (181aa) DQSAYDGKDYIALNEDLSSWTAADTAAQITQRKWEAARVAEQLRAYLEGLCVEWLR RYLENGKETLQRA (SEQ ID 004) B*57:01:05 SHSMRYFYTAMSRPGRGEPRFIAVGYVDDTQFVRFDSDAASPRMAPRAPWIEQEGP HLA04060 EYWDGETRNMKASAQTYRENLRIALRYYNQSEAGSHIIQVMYGCDVGPDGRLLRGH (181aa) DQSAYDGKDYIALNEDLSSWTAADTAAQITQRKWEAARVAEQLRAYLEGLCVEWLR RYLENGKETLQRA (SEQ ID 005) B*57:01:06 SHSMRYFYTAMSRPGRGEPRFIAVGYVDDTQFVRFDSDAASPRMAPRAPWIEQEGP HLA04456 EYWDGETRNMKASAQTYRENLRIALRYYNQSEAGSHIIQVMYGCDVGPDGRLLRGH (181aa) DQSAYDGKDYIALNEDLSSWTAADTAAQITQRKWEAARVAEQLRAYLEGLCVEWLR RYLENGKETLQRA (SEQ ID 006) B*57:01:07 SHSMRYFYTAMSRPGRGEPRFIAVGYVDDTQFVRFDSDAASPRMAPRAPWIEQEGP HLA04755 EYWDGETRNMKASAQTYRENLRIALRYYNQSEAGSHIIQVMYGCDVGPDGRLLRGH (273aa) DQSAYDGKDYIALNEDLSSWTAADTAAQITQRKWEAARVAEQLRAYLEGLCVEWLR RYLENGKETLQRADPPKTHVTHHPISDHEATLRCWALGFYPAEITLTWQRDGEDQT QDTELVETRPAGDRTFQKWAAVVVPSGEEQRYTCHVQHEGLPKPLTLRW (SEQ ID 007) B*57:01:08SHSMRYFYTAMSRPGRGEPRFIAVGYVDDTQFVRFDSDAASPRMAPRAPWIEQEGP HLA05320 EYWDGETRNMKASAQTYRENLRIALRYYNQSEAGSHIIQVMYGCDVGPDGRLLRGH (181aa) DQSAYDGKDYIALNEDLSSWTAADTAAQITQRKWEAARVAEQLRAYLEGLCVEWLR RYLENGKETLQRA (SEQ ID 008) B*57:01:09 SHSMRYFYTAMSRPGRGEPRFIAVGYVDDTQFVRFDSDAASPRMAPRAPWIEQEGP HLA05465 EYWDGETRNMKASAQTYRENLRIALRYYNQSEAGSHIIQVMYGCDVGPDGRLLRGH (181aa) DQSAYDGKDYIALNEDLSSWTAADTAAQITQRKWEAARVAEQLRAYLEGLCVEWLR RYLENGKETLQRA (SEQ ID 009) B*57:01:10 SHSMRYFYTAMSRPGRGEPRFIAVGYVDDTQFVRFDSDAASPRMAPRAPWIEQEGP HLA05563 EYWDGETRNMKASAQTYRENLRIALRYYNQSEAGSHIIQVMYGCDVGPDGRLLRGH Petição 870250111294, de 04 / 12 / 2025, pág. 64 / 79 50 / 58 (181aa) DQSAYDGKDYIALNEDLSSWTAADTAAQITQRKWEAARVAEQLRAYLEGLCVEWLR RYLENGKETLQRA (SEQ ID 010) B*57:01:11 SHSMRYFYTAMSRPGRGEPRFIAVGYVDDTQFVRFDSDAASPRMAPRAPWIEQEGP HLA06363 EYWDGETRNMKASAQTYRENLRIALRYYNQSEAGSHIIQVMYGCDVGPDGRLLRGH (273aa) DQSAYDGKDYIALNEDLSSWTAADTAAQITQRKWEAARVAEQLRAYLEGLCVEWLR RYLENGKETLQRADPPKTHVTHHPISDHEATLRCWALGFYPAEITLTWQRDGEDQT QDTELVETRPAGDRTFQKWAAVVVPSGEEQRYTCHVQHEGLPKPLTLRW (SEQ ID 011) B*57:01:12 SHSMRYFYTAMSRPGRGEPRFIAVGYVDDTQFVRFDSDAASPRMAPRAPWIEQEGP HLA07200 EYWDGETRNMKASAQTYRENLRIALRYYNQSEAGSHIIQVMYGCDVGPDGRLLRGH (181aa) DQSAYDGKDYIALNEDLSSWTAADTAAQITQRKWEAARVAEQLRAYLEGLCVEWLR RYLENGKETLQRA (SEQ ID 012) B*57:01:13 MRVTAPRTVLLLLWGAVALTETWAGSHSMRYFYTAMSRPGRGEPRFIAVGYVDDTQ HLA07801 FVRFDSDAASPRMAPRAPWIEQEGPEYWDGETRNMKASAQTYRENLRIALRYYNQS (362aa) EAGSHIIQVMYGCDVGPDGRLLRGHDQSAYDGKDYIALNEDLSSWTAADTAAQITQ RKWEAARVAEQLRAYLEGLCVEWLRRYLENGKETLQRADPPKTHVTHHPISDHEAT LRCWALGFYPAEITLTWQRDGEDQTQDTELVETRPAGDRTFQKWAAVVVPSGEEQRYTCHVQHEGLPKPLTLRWEPSSQSTVPIVGIVAGLAVLAVVVIGAVVAAVMCRRKS SGGKGGSYSQAACSDSAQGSDVSLTA (SEQ ID 013) B*57:01:14 SHSMRYFYTAMSRPGRGEPRFIAVGYVDDTQFVRFDSDAASPRMAPRAPWIEQEGP HLA08370 EYWDGETRNMKASAQTYRENLRIALRYYNQSEAGSHIIQVMYGCDVGPDGRLLRGH (181aa) DQSAYDGKDYIALNEDLSSWTAADTAAQITQRKWEAARVAEQLRAYLEGLCVEWLR RYLENGKETLQRA (SEQ ID 014) B*57:01:15 SHSMRYFYTAMSRPGRGEPRFIAVGYVDDTQFVRFDSDAASPRMAPRAPWIEQEGP HLA09723 EYWDGETRNMKASAQTYRENLRIALRYYNQSEAGSHIIQVMYGCDVGPDGRLLRGH (181aa) DQSAYDGKDYIALNEDLSSWTAADTAAQITQRKWEAARVAEQLRAYLEGLCVEWLR RYLENGKETLQRA (SEQ ID 015) B*57:01:16 SHSMRYFYTAMSRPGRGEPRFIAVGYVDDTQFVRFDSDAASPRMAPRAPWIEQEGP HLA10039 EYWDGETRNMKASAQTYRENLRIALRYYNQSEAGSHIIQVMYGCDVGPDGRLLRGH (181aa) DQSAYDGKDYIALNEDLSSWTAADTAAQITQRKWEAARVAEQLRAYLEGLCVEWLR RYLENGKETLQRA (SEQ ID 016) B*57:01:17 MRVTAPRTVLLLLWGAVALTETWAGSHSMRYFYTAMSRPGRGEPRFIAVGYVDDTQ HLA10498 FVRFDSDAASPRMAPRAPWIEQEGPEYWDGETRNMKASAQTYRENLRIALRYYNQS (337aa) EAGSHIIQVMYGCDVGPDGRLLRGHDQSAYDGKDYIALNEDLSSWTAADTAAQITQRKWEAARVAEQLRAYLEGLCVEWLRRYLENGKETLQRADPPKTHVTHHPISDHEAT LRCWALGFYPAEITLTWQRDGEDQTQDTELVETRPAGDRTFQKWAAVVVPSGEEQR YTCHVQHEGLPKPLTLRWEPSSQSTVPIVGIVAGLAVLAVVVIGAVVAAVMCRRKS S (SEQ ID 017) B*57:01:18 SHSMRYFYTAMSRPGRGEPRFIAVGYVDDTQFVRFDSDAASPRMAPRAPWIEQEGP HLA11430 EYWDGETRNMKASAQTYRENLRIALRYYNQSEAGSHIIQVMYGCDVGPDGRLLRGH (181aa) DQSAYDGKDYIALNEDLSSWTAADTAAQITQRKWEAARVAEQLRAYLEGLCVEWLR RYLENGKETLQRA (SEQ ID 018) B*57:01:19 MRVTAPRTVLLLLWGAVALTETWAGSHSMRYFYTAMSRPGRGEPRFIAVGYVDDTQ HLA11726 FVRFDSDAASPRMAPRAPWIEQEGPEYWDGETRNMKASAQTYRENLRIALRYYNQS (298aa) EAGSHIIQVMYGCDVGPDGRLLRGHDQSAYDGKDYIALNEDLSSWTAADTAAQITQ RKWEAARVAEQLRAYLEGLCVEWLRRYLENGKETLQRADPPKTHVTHHPISDHEAT LRCWALGFYPAEITLTWQRDGEDQTQDTELVETRPAGDRTFQKWAAVVVPSGEEQR YTCHVQHEGLPKPLTLRW (SEQ ID 019) B*57:01:20 SHSMRYFYTAMSRPGRGEPRFIAVGYVDDTQFVRFDSDAASPRMAPRAPWIEQEGP HLA12568 EYWDGETRNMKASAQTYRENLRIALRYYNQSEAGSHIIQVMYGCDVGPDGRLLRGH (181aa) DQSAYDGKDYIALNEDLSSWTAADTAAQITQRKWEAARVAEQLRAYLEGLCVEWLR RYLENGKETLQRA (SEQ ID 020) B*57:01:21SHSMRYFYTAMSRPGRGEPRFIAVGYVDDTQFVRFDSDAASPRMAPRAPWIEQEGP Petition 870250111294, dated 04 / 12 / 2025, pp. 65 / 79 51 / 58 HLA12884 EYWDGETRNMKASAQTYRENLRIALRYYNQSEAGSHIIQVMYGCDVGPDGRLLRGH (273aa) DQSAYDGKDYIALNEDLSSWTAADTAAQITQRKWEAARVAEQLRAYLEGLCVEWLR RYLENGKETLQRADPPKTHVTHHPISDHEATLRCWALGFYPAEITLTWQRDGEDQT QDTELVETRPAGDRTFQKWAAVVVPSGEEQRYTCHVQHEGLPKPLTLRW (SEQ ID 021) B*57:01:22 SHSMRYFYTAMSRPGRGEPRFIAVGYVDDTQFVRFDSDAASPRMAPRAPWIEQEGP HLA13005 EYWDGETRNMKASAQTYRENLRIALRYYNQSEAGSHIIQVMYGCDVGPDGRLLRGH (181aa) DQSAYDGKDYIALNEDLSSWTAADTAAQITQRKWEAARVAEQLRAYLEGLCVEWLR RYLENGKETLQRA (SEQ ID 022) B*57:02:01 MRVTAPRTVLLLLWGAVALTETWAGSHSMRYFYTAMSRPGRGEPRFIAVGYVDDTQ HLA00382 FVRFDSDAASPRMAPRAPWIEQEGPEYWDGETRNMKASAQTYRENLRIALRYYNQS (362aa) EAGSHIIQVMYGCDVGPDGRLLRGHNQYAYDGKDYIALNEDLSSWTAADTAAQITQ RKWEAARVAEQRRAYLEGLCVEWLRRYLENGKETLQRADPPKTHVTHHPISDHEAT LRCWALGFYPAEITLTWQRDGEDQTQDTELVETRPAGDRTFQKWAAVVVPSGEEQR YTCHVQHEGLPKPLTLRWEPSSQSTVPIVGIVAGLAVLAVVVIGAVVAAVMCRRKS SGGKGGSYSQAACSDSAQGSDVSLTA (SEQ ID 023) B*57:02:02 SHSMRYFYTAMSRPGRGEPRFIAVGYVDDTQFVRFDSDAASPRMAPRAPWIEQEGP HLA04435EYWDGETRNMKASAQTYRENLRIALRYYNQSEAGSHIIQVMYGCDVGPDGRLLRGH (181aa) NQYAYDGKDYIALNEDLSSWTAADTAAQITQRKWEAARVAEQRRAYLEGLCVEWLR RYLENGKETLQRA (SEQ ID 024) B*57:03:01 MRVTAPRTVLLLLWGAVALTETWAGSHSMRYFYTAMSRPGRGEPRFIAVGYVDDTQ HLA00383 FVRFDSDAASPRMAPRAPWIEQEGPEYWDGETRNMKASAQTYRENLRIALRYYNQS (362aa) EAGSHIIQVMYGCDVGPDGRLLRGHNQYAYDGKDYIALNEDLSSWTAADTAAQITQ RKWEAARVAEQLRAYLEGLCVEWLRRYLENGKETLQRADPPKTHVTHHPISDHEAT LRCWALGFYPAEITLTWQRDGEDQTQDTELVETRPAGDRTFQKWAAVVVPSGEEQR YTCHVQHEGLPKPLTLRWEPSSQSTVPIVGIVAGLAVLAVVVIGAVVAAVMCRRKS SGGKGGSYSQAACSDSAQGSDVSLTA (SEQ ID 025) B*57:03:02 SHSMRYFYTAMSRPGRGEPRFIAVGYVDDTQFVRFDSDAASPRMAPRAPWIEQEGP HLA01289 EYWDGETRNMKASAQTYRENLRIALRYYNQSEAGSHIIQVMYGCDVGPDGRLLRGH (273aa) NQYAYDGKDYIALNEDLSSWTAADTAAQITQRKWEAARVAEQLRAYLEGLCVEWLR RYLENGKETLQRADPPKTHVTHHPISDHEATLRCWALGFYPAEITLTWQRDGEDQT QDTELVETRPAGDRTFQKWAAVVVPSGEEQRYTCHVQHEGLPKPLTLRW (SEQ ID 026) B*57:04:01 SHSMRYFYTAMSRPGRGEPRFIAVGYVDDTQFVRFDSDAASPRMAPRAPWIEQEGP HLA00384EYWDGETRNMKASAQTYRENLRIALRYYNQSEAGSHIIQVMYGCDVGPDGRLLRGY (273aa) DQDAYDGKDYIALNEDLSSWTAADTAAQITQRKWEAARVAEQRRAYLEGLCVEWLR RYLENGKETLQRADPPKTHVTHHPISDHEATLRCWALGFYPAEITLTWQRDGEDQT QDTELVETRPAGDRTFQKWAAVVVPSGEEQRYTCHVQHEGLPKPLTLRW (SEQ ID 027) B*57:04:02 SHSMRYFYTAMSRPGRGEPRFIAVGYVDDTQFVRFDSDAASPRMAPRAPWIEQEGP HLA14153 EYWDGETRNMKASAQTYRENLRIALRYYNQSEAGSHIIQVMYGCDVGPDGRLLRGY (181aa) DQDAYDGKDYIALNEDLSSWTAADTAAQITQRKWEAARVAEQRRAYLEGLCVEWLR RYLENGKETLQRA (SEQ ID 028) B*57:05 MRVTAPRTVLLLLWGAVALTETWAGSHSMRYFYTAMSRPGRGEPRFIAVGYVDDTQ HLA00385 FVRFDSDAASPRMAPRAPWIEQEGPEYWDGETRNMKASAQTYRENLRIALRYYNQS (362aa) EAGSHIIQRMYGCDLGPDGRLLRGYNQYAYDGKDYIALNEDLSSWTAADTAAQITQ RKWEAARVAEQRRAYLEGLCVEWLRRYLENGKETLQRADPPKTHVTHHPISDHEAT LRCWALGFYPAEITLTWQRDGEDQTQDTELVETRPAGDRTFQKWAAVVVPSGEEQR YTCHVQHEGLPKPLTLRWEPSSQSTVPIVGIVAGLAVLAVVVIGAVVAAVMCRRKS SGGKGGSYSQAACSDSAQGSDVSLTA (SEQ ID 029) B*57:06 MRVTAPRTVLLLLWGAVALTETWAGSHSMRYFYTAMSRPGRGEPRFIAVGYVDDTQ HLA01074FVRFDSDAASPRMAPRAPWIEQEGPEYWDGETRNMKASAQTYRENLRIALRYYNQS EAGSHIIQVMYGCDVGPDGRLLRGHDQSAYDGKDYIALNEDLSSWTAADTAAQIIQ Petition 870250111294, dated 04 / 12 / 2025, pp. 66 / 79 52 / 58 (362aa) RKWEAARVAEQLRAYLEGLCVEWLRRYLENGKETLQRADPPKTHVTHHPISDHEAT LRCWALGFYPAEITLTWQRDGEDQTQDTELVETRPAGDRTFQKWAAVVVPSGEEQR YTCHVQHEGLPKPLTLRWEPSSQSTVPIVGIVAGLAVLAVVVIGAVVAAVMCRRKS SGGKGGSYSQAACSDSAQGSDVSLTA (SEQ ID 030) B*57:07 SHSMRYFYTAMSRPGRGEPRFIAVGYVDDTQFVRFDSDAASPRMAPRAPWIEQEGP HLA01192 EYWDGETRNMKASAQTYRENLRIALRYYNQSEAGSHIIQVMYGCDVGPDGRLLRGH (181aa) NQYAYDGKDYIALNEDLSSWTAADTAAQITQRKWEAARVAEQLRAYLEGLCVESLR RYLENGKETLQRA (SEQ ID 031) B*57:08 SHSMRYFYTAMSRPGRGEPRFIAVGYVDDTQFVRFDSDAASPRMAPRAPWIEQEGP HLA01461 EYWDGETRNMKASAQTYRENLRIALPYYNQSEAGSHIIQVMYGCDVGPDGRLLRGH (181aa) DQSAYDGKDYIALNEDLSSWTAADTAAQITQRKWEAARVAEQLRAYLEGLCVEWLR RYLENGKETLQRA (SEQ ID 032) B*57:09 SHSMRYFYTAMSRPGRGEPRFIAVGYVDDTQFVRFDSDAASPRMAPRAPWIEQEGP HLA01485 EYWDGETRNMKASAQTYRENLRIALRYYNQSEAGSHIIQVMYGCDVGPDGRLLRGH (181aa) NQYAYDGKDYIALNEDLSSWTAADTAAQITQRKWEAAREAEQDRAYLEGLCVEWLR RYLENGKETLQRA (SEQ ID 033) B*57:10 SHSMRYFYTSVSRPGRGEPRFIAVGYVDDTQFVRFDSDAASPRMAPRAPWIEQEGP HLA02307EYWDGETRNMKASAQTYRENLRIALRYYNQSEAGSHIIQVMYGCDVGPDGRLLRGH (181aa) DQSAYDGKDYIALNEDLSSWTAADTAAQITQRKWEAARVAEQLRAYLEGLCVEWLR RYLENGKETLQRA (SEQ ID 034) B*57:11 MRVTAPRTVLLLLWGAVALTETWAGSHSMRYFYTAMSRPGRGEPRFIAVGYVDDTQ HLA02676 FVRFDSDAASPRMAPRAPWIEQEGPEYWDGETRNMKASAQTYRENLRIALRYYNQS (362aa) EAGSHTLQWMYGCDVGPDGRLLRGHDQSAYDGKDYIALNEDLSSWTAADTAAQITQ RKWEAARVAEQLRAYLEGLCVEWLRRYLENGKETLQRADPPKTHVTHHPISDHEAT LRCWALGFYPAEITLTWQRDGEDQTQDTELVETRPAGDRTFQKWAAVVVPSGEEQR YTCHVQHEGLPKPLTLRWEPSSQSTVPIVGIVAGLAVLAVVVIGAVVAAVMCRRKS SGGKGGSYSQAACSDSAQGSDVSLTA (SEQ ID 035) B*57:12 SHSMRYFYTAMSRPGRGEPRFIAVGYVDDTQFVRFDSDAASPRMAPRAPWIEQEGP HLA02888 EYWDGETRNMKASAQTYRESLRNLRGYYNQSEAGSHIIQVMYGCDVGPDGRLLRGH (181aa) NQYAYDGKDYIALNEDLSSWTAADTAAQITQRKWEAARVAEQRRAYLEGLCVEWLR RYLENGKETLQRA (SEQ ID 036) B*57:13 SHSMRYFYTAMSRPGRGEPRFIAVGYVDDTQFVRFDSDAASPRMAPRAPWIEQEGP HLA02966 EYWDGETRNMKASAQTYRENLRIALRYYNQSEAGSHIIQVMYGCDVGPDGRLLRGH (181aa) DQSAYDGKDYIALNEDLRSWTAADTAAQITQRKWEAAREAEQRRAYLEGECVEWLR RYLENGKETLQRA (SEQ ID037) B*57:14:01 SHSMRYFYTAMSRPGRGEPRFIAVGYVDDTQFVRFDSDAASPRMAPRAPWIEQEGP HLA03129 EYWDGETRNMKASAQTYRENLRIALRYYNQSEAGSHIIQVMYGCDVGPDGRLLRGH (181aa) HLA12293 EYWDGETRNMKASAQTYRENLRIALRYYNQSEAGSHIIQVMYGCDVGPDGRLLRGH (181aa) HLA03147 B*57:16 SHSMRYFYTAMSRPGRGEPRFIAVGYVDDTQFVRFDSDAASPRMEPRAPWIEQEGP HLA03150 EYWDGETRNMKASAQTYRENLRIALRYYNQSEAGSHIIQVMYGCDVGPDGRLLRGH (181aa) DQSAYDGKDYIALNEDLSSWTAADTAAQITQRKWEAARVAEQLRAYLEGLCVEWLR RYLENGKETLQRA (SEQ ID 041) Petition 870250111294, on 12 / 04 / 2025, page. 67 / 79 53 / 58 B*57:17 SHSMRYFYTAMSRPGRGEPRFIAVGYVDDTQFVRFDSDAASPRMAPRAPWIEQEGP HLA03320 EYWDGETRNMKASAQTYRENLRIALRYYNQSEAGSHIIQVMYGCDVGPDGRLLRGH (181aa) NQYAYDGKDYIDLNEDLSSWTAADTAAQITQRKWEAARVAEQLRAYLEGLCVEWLR RYLENGKETLQRA (SEQ ID 042) B*57:18 SHSMRYFYTAMSRPGRGEPRFIAVGYVDDTQFVRFDSDAASPRMAPRAPWIEQEGP HLA03506 EYWDGETRNMKASAQTYRENLRIALRYYNQSEAGSHIIQVMYGCDVGPDGRLLRGH (181aa) DQSAYDGKDYIALNEDLSSWTAAYTAAQITQRKWEAARVAEQLRAYLEGLCVEWLR RYLENGKETLQRA (SEQ ID 043) B*57:19 SHSMRYFYTAMSRPGRGEPRFIAVGYVDDTQFVRFDSDAASPRMAPRAPWIEQEGP HLA03507 EYWDGETRNMKASAQTYRENLRIALRYYNQSEAGSHIIQVMYGCDVGPDGRLLRGH (181aa) DQSAYDGKDYIALNEDLSSWTAADTAAQITQRKWEAARVAEQRRAYLEGLCVEWLR RYLENGKETLQRA (SEQ ID 044) B*57:20 SHSMRYFYTAMSRPGRGEPRFIAVGYVDDTQFVRFDSDAASPRMAPRAPWIEQEGP HLA03666 EYWDGKTRNMKASAQTYRENLRIALRYYNQSEAGSHIIQVMYGCDVGPDGRLLRGH (181aa) DQSAYDGKDYIALNEDLSSWTAADTAAQITQRKWEAARVAEQLRAYLEGLCVEWLR RYLENGKETLQRA (SEQ ID 045) B*57:21 SHSMRYFYTAMSRPGRGEPRFIAVGYVDDTQFVRFDSDAASPRMAPRAPWIEQEGP HLA03675EYWDGETRNMKASAQTYRENLRIALRYYNQSEAGSHVIQVMYGCDVGPDGRLLRGH (181aa) DQSAYDGKDYIALNEDLSSWTAADTAAQITQRKWEAARVAEQLRAYLEGLCVEWLR RYLENGKETLQRA (SEQ ID 046) B*57:22 SHSMRYFYTAMSRPGRGEPRFIAVGYVDDTQFVRFDSDAASPRMAPRAPWIEQEGP HLA03904 EYWDGETRNMKASAQTYRENLRIALRYYNQSEAGSHIIQVMYGCDVGPDGRLLRGH (181aa) DQSAYDGKDYIALNEDLSSWTAADTAAQITQRKWEAAREAEQLRAYLEGLCVEWLR RYLENGKETLQRA (SEQ ID 047) B*57:23 SHSMRYFYTAMSRPGRGESRFIAVGYVDDTQFVRFDSDAASPRMAPRAPWIEQEGP HLA04046 EYWDGETRNMKASAQTYRENLRIALRYYNQSEAGSHIIQVMYGCDVGPDGRLLRGH (181aa) DQSAYDGKDYIALNEDLSSWTAADTAAQITQRKWEAARVAEQLRAYLEGLCVEWLR RYLENGKETLQRA (SEQ ID 048) B*57:24 SHSMRYFYTAMSRPGRGEPRFIAVGYVDDTQFVRFDSDAASPRMAPRAPWIEQEGP HLA03984 EYWDGETRNMKASAQTYRENLRIALRYYNQSEAGSHIIQVMYGCDVGPDGRLLRGH (181aa) DQSAYDGKDYIALNEDLSSWTAADTAAQITQRKWEAARVAEQDRAYLEGLCVEWLR RYLENGKETLQRA (SEQ ID 049) B*57:25 SHSMRYFYTAMSRPGRGEPRFIAVGYVDDTQFVRFDSDAASPRMAPRAPWIEQEGP HLA03986 EYWDGETRNMKASAQTYRENLRIALRYYNQSEAGSHIIQVMYGCDVGPDGRLLRGH (181aa)DQSAYDGKDYIALNEDLSSWTAADTAAQITQRKWEAARVAEQLRAYLEGECVEWLR RYLENGKETLQRA (SEQ ID 050) B*57:26 SHSMRYFYTAMSRPGRGEPRFIAVGYVDDTQFVRFDSDAASPRMAPRAPWIEQEGP HLA04203 EYWDGETRNMKASAQTYRENLRIALRYYNQSEAGSHIIQVMYGCDVGPDGRLLRGH (181aa) DQSAYDGKDYIALNEDLSSWTAADTAAQITQRKWEAARVAEQLRAYLEGTCVEWLR RYLENGKETLQRA (SEQ ID 051) B*57:27 SHSMRYFYTAMSRPGRGEPRFIAVGYVDDTQFVRFDSDAASPRMAPRAPWIEQEGP HLA04452 EYWDGETRNMKASAQTYRENLRIALRYYNQSEAGSHIIQVMYGCDVGPDGRLLRGH (181aa) DQSAYDGKDYIALNEDLSSWTAADTAAQITQRKWEAARVAEHLRAYLEGLCVEWLR RYLENGKETLQRA (SEQ ID 052) B*57:28N SHSMRYFYTAMSRPGRGEPRFIAVGYVDDTQFVRFDSDAASPRMAPRAPWIEQEGP HLA04401 EYWDGETRNMKASAQTYRENLRIALRYYNQSEAGSHIIQVMYGCDVGPDGRLLRGH (115aa) NQX (SEQ ID 053) B*57:29 MRVTAPRTVLLLLWGAVALTETWAGSHSMRYFYTAMSRPGRGEPRFIAVGYVDDTQ HLA04576 FVRFDSDAASPRMAPRAPWIEQEGPEYWDGETRNMKASAQTYRENLRIALRYYNQS (362aa) EAGSHIIQVMYGCDVGPDGRLLRGHDQSAYDGKDYIALNEDLSSWTAADTAAQITQ RKWEAARVAEQLRAYLEGLCVEWLRRYLENGKETLQRADPPKTHVTHHPISDHEAT Petição 870250111294, de 04 / 12 / 2025, pág. 68 / 79 54 / 58 LRCWALGFYPVEITLTWQRDGEDQTQDTELVETRPAGDRTFQKWAAVVVPSGEEQR YTCHVQHEGLPKPLTLRWEPSSQSTVPIVGIVAGLAVLAVVVIGAVVAAVMCRRKS SGGKGGSYSQAACSDSAQGSDVSLTA (SEQ ID 054) B*57:30 SHSMRYFYTAMSRPGRGEPRFIAVGYVDDTQFVRFDSDAASPRMAPRAPWIEQEGP HLA04703 EYWDGETRNMKASAQTYRENLRIALRYYNQSEAGSHIIQVMYGCDVGPDGRLLRGH (181aa) DQSAYDGKDYIALNEDLSSWTAADTAAQITQRKWEAARAAEQRRAYLEGLCVEWLR RYLENGKETLQRA (SEQ ID 055) B*57:31 SHSMRYFYTAMSRPGRGEPRFIAVGYVDDTQFVRFDSDAASPRMAPRAPWIEQEGP HLA04848 EYWDGETRNMKASAQTYRENLRIALRYYNQSEAGSHIIQVMYGCDVGPDGRLLRGH (181aa) DQSAYDGKDYIALNEDLRSWTAADTAAQITQRKWEAARVAEQLRAYLEGLCVEWLR RYLENGKETLQRA (SEQ ID 056) B*57:32 SHSMRYFYTAMSRPGRGEPRFIAVGYVDDTQFVRFDSDAASPRMAPRAPWIEQEGP HLA05424 EYWDGETRNMKASAQTYRENLRIALRYYNQSEAGSHIIQVMYGCDVGPDGRLLRGY (181aa) HQDAYDGKDYIALNEDLSSWTAADTAAQITQRKWEAARVAEQLRAYLEGLCVEWLR RYLENGKETLQRA (SEQ ID 057) B*57:33 SHSMRYFYTAMSRPGRGEPRFIAVGYVDDTQFVRFDSDAASPRMAPRAPWIEQEGP HLA05476 EYWDGETRNMKASAQTYRENLRIALRYYNQSEAGSHIIQVMYGCDVGPDERL (181aa)LRGHDQSAYDGKDYIALNEDLSSWTAADTAAQITQRKWEAARVAEQLRAYLEGLCV EWLRRYLENGKETLQRA (SEQ ID 058) B*57:34 SHSMRYFYTAMSRPGRGEPRFIAVGYVDDTQFVRFDSDAASRRMAPRAPWIEQEGP HLA05503 EYWDGETRNMKASAQTYRENLRIALRYYNQSEAGSHIIQVMYGCDVGPDGRLLRGH (181aa) DQSAYDGKDYIALNEDLSSWTAADTAAQITQRKWEAARVAEQLRAYLEGLCVEWLR RYLENGKETLQRA (SEQ ID 059) B*57:35 SHSMRYFYTAMSRPGRGEPRFIAVGYVDDTQFVRFDSDAASPRMAPRAPWIEQEGP HLA05513 KYWDGETRNMKASAQTYRENLRIALRYYNQSEAGSHIIQVMYGCDVGPDGRLLRGH (181aa) DQSAYDGKDYIALNEDLSSWTAADTAAQITQRKWEAARVAEQLRAYLEGLCVEWLR RYLENGKETLQRA (SEQ ID 060) B*57:36 SHSMRYFYTAMSRPGRGEPRFIAVGYVDDTQFVRFDSDAASPRMAPRAPWIEQEGP HLA05562 EYWDGETRHMKASAQTYRENLRIALRYYNQSEAGSHIIQVMYGCDVGPDGRLLRGH (181aa) DQSAYDGKDYIALNEDLSSWTAADTAAQITQRKWEAARVAEQLRAYLEGLCVEWLR RYLENGKETLQRA (SEQ ID 061) B*57:37 SHSMRYFYTAMSRPGRGEPRFIAVGYVDDTQFVRFDSDAASPRMAPRAPWIEQEGP HLA05876 EYWDGETRNMKASAQTYRENLRIALRYYNQSEAGSHIIQVMYGCDVGPDGRLLRGH (273aa) DQSAYDGKDYIALNEDLSSWTAADTAAQITQRKWEAARVAEQLRAYLEGLCVEWLRRYLENGKETLQRADPPKTHVTHHPISDHEATLRCWALGFYPAEITLTWQRDGEDQT QDTELVETRPAGDRTFQKWAAVVVPSGEEQRYTCHVQHEGLPKHLTLRW (SEQ ID 062) B*57:38 SHSMRYFYTAMSRPGRGEPRFIAVGYVDDTQFVRFDSDAASPRMAPRAPWIEQEGP HLA05958 EYWDGETRNMKASAQTYRETLRIALRYYNQSEAGSHIIQVMYGCDVGPDGRLLRGH (181aa) DQSAYDGKDYIALNEDLSSWTAADTAAQITQRKWEAARVAEQLRAYLEGLCVEWLR RYLENGKETLQRA (SEQ ID 063) B*57:39 SHSMRYFHTAMSRPGRGEPRFIAVGYVDDTQFVRFDSDAASPRMAPRAPWIEQEGP HLA06229 EYWDGETRNMKASAQTYRENLRIALRYYNQSEAGSHIIQVMYGCDVGPDGRLLRGH (181aa) NQYAYDGKDYIALNEDLSSWTAADTAAQITQRKWEAARVAEQLRAYLEGLCVEWLR RYLENGKETLQRA (SEQ ID 064) B*57:40 SHSMRYFYTAMSRPGRGEPRFIAVGYVDDTQFVRFDSDAASPRMAPRAPWIEQEGP HLA06240 EYWDGETRNMKASAQTYRENLRIALRYYNQSEAGSHNIQVMYGCDVGPDGRLLRGH (181aa) DQSAYDGKDYIALNEDLSSWTAADTAAQITQRKWEAARVAEQLRAYLEGLCVEWLR RYLENGKETLQRA (SEQ ID 065) B*57:41 SHSMRYFYTAMSRPGRGEPRFIAVGYVDDTQFVRFDSDAASPRMAPRAPWIEQEGP HLA06241 EYWDGETRNMKASAQTYRENLRIALRYYNQSEAGSHIIQVMYGCDVGPDGRLLRGY (181aa) DQSAYDGKDYIALNEDLSSWTAADTAAQITQRKWEAARVAEQLRAYLEGLCVEWLR Petition 870250111294, dated 04 / 12 / 2025, pp. 69 / 79 55 / 58 RYLENGKETLQRA (SEQ ID 066) B*57:42 SHSMRYFYTAMSRPGRGEPRFIAVGYVDDTQFVRFDSDAASPRMAPRAPWIEQEGP HLA06249 EYWDGETRNMKASAQTYRENLRIALRYYNQSEAGSHIIQVMYGCDVGPDGRLLRGH (181aa) NQYAYDGKDYIALNEDLSSWTAADTAAQITQRKWEEARVAEQRRAYLEGLCVEWLR RYLENGKETLQRA (SEQ ID 067) B*57:43 SHSMRYFYTAMSRPGRGEPRFIAVGYVDDTQFVRFDSDAASPRMAPRAPWIEQEGP HLA06250 EYWDGETRNMKASAQTYRENLRIALRYYNQSEAGSHIIQVMYGCDVGPDGRLLRGH (181aa) DQSAYDGKDYIALNEDLSSWTAADTAAQITQRKWEAARVAEQLRAYLEGPCVEWLR RYLENGKETLQRA (SEQ ID 068) B*57:44 SHSMRYFYTAMSRPGLGEPRFIAVGYVDDTQFVRFDSDAASPRMAPRAPWIEQEGP HLA06315 EYWDGETRNMKASAQTYRENLRIALRYYNQSEAGSHIIQVMYGCDVGPDGRLLRGH (181aa) DQSAYDGKDYIALNEDLSSWTAADTAAQITQRKWEAARVAEQLRAYLEGLCVEWLR RYLENGKETLQRA (SEQ ID 069) B*57:45 SHSMRYFYTAMSRPGRGEPRFIAVGYVDDTQFVRFDSDATSPRKEPRAPWIEQEGP HLA06683 EYWDGETRNMKASAQTYRENLRIALRYYNQSEAGSHIIQVMYGCDVGPDGRLLRGH (181aa) DQSAYDGKDYIALNEDLSSWTAADTAAQITQRKWEAARVAEQLRAYLEGLCVEWLR RYLENGKETLQRA (SEQ ID 070) B*57:46 SHSMRYFYTAMSRPGRGEPRFIAVGYVDDTQFVRFDSDAASPRMAPRAPWIEQEGP HLA06688EYWDGETRNMKASAQTYRENLRIALRYYNQSEAGSHIIQVMYGCDVGPDGRLLRGH (181aa) NQYAYDGKDYIALNEDLSSWTAADTAAQITQRKWEAACVAEQLRAYLEGLCVEWLR RYLENGKETLQRA (SEQ ID 071) B*57:47 SHSMRYFYTAMSRPGRGEPRFIAVGYVDDTQFVRFDSDAASPRMAPRAPWIEQEGP HLA06700 EYWDGETRNMKASAQTYRENLRIALRYYNQSEAGSHIIQVMYGCDVGPDGRLLRGH (181aa) DQSAYDGKDYIALNEDLSCWTAADTAAQITQRKWEAARVAEQLRAYLEGLCVEWLR RYLENGKETLQRA (SEQ ID 072) B*57:48 SHSMRYFYTAMSRPGRGEPRFIAVGYVDDTQFVRFDSDAASPRMAPRAPWIEQEGP HLA06883 EYWDGETRNMKASAQTYRENLRIALRYYNQSEAGSHIIQVMYGCDVGPDGPLLRGH (273aa) DQSAYDGKDYIALNEDLSSWTAADTAAQITQRKWEAARVAEQLRAYLEGLCVEWLR RYLENGKETLQRADPPKTHVTHHPISDHEATLRCWALGFYPAEITLTWQRDGEDQT QDTELVETRPAGDRTFQKWAAVVVPSGEEQRYTCHVQHEGLPKPLTLRW (SEQ ID 073) B*57:49 SHSMRYFDTAMSRPGRGEPRFIAVGYVDDTQFVRFDSDAASPRMAPRAPWIEQEGP HLA06942 EYWDGETRNMKASAQTYRENLRIALRYYNQSEAGSHIIQVMYGCDVGPDGRLLRGH (181aa) DQSAYDGKDYIALNEDLSSWTAADTAAQITQRKWEAARVAEQLRAYLEGLCVEWLR RYLENGKETLQRA (SEQ ID 074) B*57:50 SHSMRYFYTAMSRPGRGEPRFIAVGYVDDTQFVRFDSDAASPRMAPRAPWIEQEGP HLA06949EYWDGETRNMKASAQTYRENLRIALRYYNQSEAGSHIIQVMYGCDVGPDGRLLRGH (181aa) DQSAYDGKDYIALNEDLSSWTAADTAAQITQGKWEAARVAEQLRAYLEGLCVEWLR RYLENGKETLQRA (SEQ ID 075) B*57:51 SHSMRYFHTAMSRPGRGEPRFITVGYVDDTLFVRFDSDATSPRKEPRAPWIEQEGP HLA06974 EYWDGETRNMKASAQTYRENLRIALRYYNQSEAGSHIIQVMYGCDVGPDGRLLRGH (181aa) DQSAYDGKDYIALNEDLSSWTAADTAAQITQRKWEAARVAEQLRAYLEGLCVEWLR RYLENGKETLQRA (SEQ ID 076) B*57:52 SHSMRYFYTAMSRPGRGEPRFIAVGYVDDTQFVRFDSDAASPRMAPRAPWIEQEGP HLA06989 EYWDGETRNMKASAQTYRENLRIALRYYNQSEAGSHIIQVMYGCDVGPDGRLLRGH (181aa) DQSAYDGKDYIALNEDLSSWTAADTAAQITQRKWEAARVAEQLRASLEGLCVEWLR RYLENGKETLQRA (SEQ ID 077) B*57:53 SHSMRYFYTAMSRPGRGEPRFIAVGYVDDTQFVRFDSDAASPRMAPRAPWIEQEGP HLA07455 EYWDGETRNMKASAQTYRENLRIALRYYNQSEAGSHIIQVMYGCDVGPDGRLLRGH (181aa) DQSTYDGKDYIALNEDLSSWTAADTAAQITQRKWEAARVAEQLRAYLEGLCVEWLR RYLENGKETLQRA (SEQ ID 078) B*57:54 SHSMRYFYTAMSRPGRGEPRFIAVGYVDDTQFVRFDSDAASPRMAPRAPWIEQEGP HLA07456 EYWDGETRNMKASAQTYRENLRIALRYYNQSEAGSHIIQVMYGCDVGPDGRLLRGH Petition 870250111294, dated 04 / 12 / 2025, pp. 70 / 79 56 / 58 (181aa) DQSAYDGKDYIALNEDLSSWTAADKAAQITQRKWEAARVAEQLRAYLEGLCVEWLR RYLENGKETLQRA (SEQ ID 079) B*57:55 SHSMRYFYTAMSRPGRGEPRFIAVGYVDDTQFVRFDSDAASPRMAPRAPWIEQEGP HLA07545 EYWDGETRNMKASAQTYRENLRIALRYYNQSEAGSHIIQVMYGCDVGPDGRLLRGH (273aa) DQSAYDGKDYIALNEDLSSWTAADTAAQITQRKWEAARVAEQLRAYLEGLCVEWLR RYLENGKETLQRADPPKTHVTHHPISDHEATLRCWALGFYPAEITLTWQRDGEDQT QDTKLVETRPAGDRTFQKWAAVVVPSGEEQRYTCHVQHEGLPKPLTLRW (SEQ ID 080) B*57:56 SHSMRYFYTAMSRPGRGEPRFIAVGYVDDTQFVRFDSDAASPRMAHRAPWIEQEGP HLA07708 EYWDGETRNMKASAQTYRENLRIALRYYNQSEAGSHIIQVMYGCDVGPDGRLLRGH (181aa) DQSAYDGKDYIALNEDLSSWTAADTAAQITQRKWEAARVAEQLRAYLEGLCVEWLR RYLENGKETLQRA (SEQ ID 081) B*57:57 SHSMRYFYTAMSRPGRGEPRFIAVGYVDDTQFVRFDSDAASPRMAPRAPWIEQEGP HLA07748 EYWDGETRNMKASAQTYRENLRIALRYYNQSEAGSHIIQVMYGCDVGPDGRLLRGH (273aa) NQYAYDGKDYIALNEDLSSWTAADTAAQITQRKWEAAREAEQLRAYLEGLCVEWLR RYLENGKETLQRADPPKTHVTHHPISDHEATLRCWALGFYPAEITLTWQRDGEDQT QDTELVETRPAGDRTFQKWAAVVVPSGEEQRYTCHVQHEGLPKPLTLRW (SEQ ID 082) B*57:58SHSMRYFYTAMSRPGRGEPRFISVGYVDDTQFVRFDSDAASPRMAPRAPWIEQEGP HLA08073 EYWDGETRNMKASAQTYRENLRIALRYYNQSEAGSHIIQVMYGCDVGPDGRLLRGH (181aa) DQSAYDGKDYIALNEDLSSWTAADTAAQITQRKWEAARVAEQLRAYLEGLCVEWLR RYLENGKETLQRA (SEQ ID 083) B*57:59 SHSMRYFYTAMSRPGRGEPRFIAVGYVDDTQFVRFDSDAASPRMAPRAPWIEQEGP HLA08294 EYWDGETRNMKASAQTYRENLRIALRYYNQSEAGSHIIQVMYGCDVGPDGRLLRGH (273aa) DQSAYDGKDYIALNEDLSSWTAADTAAQISQRKLEAARVAEQLRAYLEGLCVEWLR RYLENGKETLQRADPPKTHVTHHPISDHEATLRCWALGFYPAEITLTWQRDGEDQT QDTELVETRPAGDRTFQKWAAVVVPSGEEQRYTCHVQHEGLPKPLTLRW (SEQ ID 084) B*57:60 SHSMRYFYTAMSRPGRGEPRFIAVGYVDDTQFVRFDSDAASPRMAPRAPWIEQEGP HLA08371 EYWDGETRNMKASAQTYRESLRIALRYYNQSEAGSHIIQVMYGCDVGPDGRLLRGH (181aa) DQSAYDGKDYIALNEDLSSWTAADTAAQITQRKWEAARVAEQLRAYLEGLCVEWLR RYLENGKETLQRA (SEQ ID 085) B*57:61 SHSMRYFYTAMSRPGRGEPRFIAVGYVDDTQFVRFDSDAASPRMAPRAPWIEQEGP HLA08927 EYWDGETRNMKASAQTYRENLRIALRYYNQSEAGSHIIQVMYGCDVGPDGRLLRGH (181aa) DQSAYDGKDYIALNEDLSSWTAADTAAQITQRKWEAARVAEQLRAYLGGLCVEWLR RYLENGKETLQRA (SEQ ID 086) B*57:62SHSMRYFYTAMSRPGRGEPRFIAVGYVDDTQFVRFDSDAASPRMAPRAPWIEQEGP HLA08997 EYWDGEKRNMKASAQTYRENLRIALRYYNQSEAGSHIIQVMYGCDVGPDGRLLRGH (181aa) DQSAYDGKDYIALNEDLSSWTAADTAAQITQRKWEAARVAEQLRAYLEGLCVEWLR RYLENGKETLQRA (SEQ ID 087) B*57:63 SHSMRYFYTAMSRPGRGEPRFIAVGYVDDTQFVRFDSDAASPRMAPRAPWIEQEGP HLA09303 EYWDGETRNMKASAQTYRENLRIALRYYNQSEAGSHIIQVMYGCDVGPDGRLLRGH (181aa) NQYAYDGKDYIALNEDLSSWTAADTAAQITQRKWEAAREAEQRRAYLEGLCVEWLR RYLENGKETLQRA (SEQ ID 088) B*57:64 SHSMRYFYTAMSRPGRGEPRFIAVGYVDDTQFVRFDSDAASPRMAPRAPWIEQEGP HLA09312 EYWDGETRNMKASAQTYRENLRIALRYYNQSEAGSHIIQVMYGCDVGPDGRLLRGH (181aa) DQSAYDGKDYIALNEDLSSWTAADTAAQITQRKWEAACVAEQLRAYLEGLCVEWLR RYLENGKETLQRA (SEQ ID 089) B*57:65 SHSMRYFYTAMSRPGRGEPRFIAVGYVDDTQFVRFDSDAASPRMAPRAPWIEQEGP HLA09577 EYWDGETRNMKASAQTYRENLRIALRYYNQSEAGSHIIQVMYGCDVGPDGRLLRGH (181aa) DQSAYDGKDYIALNEDLSSWTAADTAAQITQRKWEAVRVAEQLRAYLEGLCVEWLR RYLENGKETLQRA (SEQ ID 090) B*57:66 SHSMRYFYTAMSRPGRGEPRFIAVGYVDDTQFVRFDSDAASPRMAPRAPWIEQEGP Petition 870250111294, dated 04 / 12 / 2025, pp. 71 / 79 57 / 58 HLA09909 EYWDGETRNMKASAQTYRENLRIALRYYNQSEAGSHIIQVMYGCDVGPDGRLLRGH (181aa) NQYAYDGKDYIALNEDLSSRTAADTAAQITQRKWEAARVAEQLRAYLEGLCVEWLR RYLENGKETLQRA (SEQ ID 091) B*57:67:01 SHSMRYFYTAMSRPGRGEPRFIAVGYVDDTQFVRFDSDAASPRMAPRAPWIEQEGP HLA10038 EYWDGETRNMKASAQTYRENLRIALRYYNQSEAGSHIIQVMYGCDLGPDGRLLRGH (181aa) DQSAYDGKDYIALNEDLSSWTAADTAAQITQRKWEAARVAEQLRAYLEGLCVEWLR RYLENGKETLQRA (SEQ ID 092) B*57:67:02 SHSMRYFYTAMSRPGRGEPRFIAVGYVDDTQFVRFDSDAASPRMAPRAPWIEQEGP HLA14152 EYWDGETRNMKASAQTYRENLRIALRYYNQSEAGSHIIQVMYGCDLGPDGRLLRGH (181aa) DQSAYDGKDYIALNEDLSSWTAADTAAQITQRKWEAARVAEQLRAYLEGLCVEWLR RYLENGKETLQRA (SEQ ID 093) B*57:68 SHSMRYFYTAMSRPGRGEPRFIAVGYVDDTQFVRFDSDAASPRMAPRAPWIEQEGP HLA10040 EYWDGETRNMKASAQTYRENLRIALRYYNQSEAGSHIIQVMYGCDVGPDGRLLRGH (181aa) DQSAYDGKDYIALNEDLSSWTAADTAAQITKRKWEAARVAEQLRAYLEGLCVEWLR RYLENGKETLQRA (SEQ ID 094) B*57:69 SHSMRYFYTAMSRPGRGEPRFITVGYVDDTLFVRFDSDATSPRKEPRAPWIEQEGP HLA10408 EYWDGETRNMKASAQTYRENLRIALRYYNQSEAGSHIIQVMYGCDVGPDGRLLRGH (181aa)DQSAYDGKDYIALNEDLSSWTAADTAAQITQRKWEAARVAEQLRAYLEGLCVEWLR RYLENGKETLQRA (SEQ ID 095) B*57:70 SHSMRYFYTAMSRPGRGEPRFIAVGYVDDTQFVRFDSDAASPRMAPRAPWIEQEGP HLA11328 EYWDGETRNMKASAQTYRENLRIALRYYNQSEAGSHIIQVMYGCDVGPDGRLLRGH (181aa) NQYAYDGKDYIALNEDLSSWTAADTAAQITQRKWEAARVAEQLRAYLEGLCVECLR RYLENGKETLQRA (SEQ ID 096) B*57:71 SHSMRYFYTAMSRPGRGEPRFITVGYVDDTQFVRFDSDATSPRMAPRAPWIEQEGP HLA11950 EYWDGETRNMKASAQTYRENLRIALRYYNQSEAGSHIIQVMYGCDVGPDGRLLRGH (273aa) DQSAYDGKDYIALNEDLSSWTAADTAAQITQRKWEAARVAEQLRAYLEGLCVEWLR RYLENGKETLQRADPPKTHVTHHPISDHEATLRCWALGFYPAEITLTWQRDGEDQT QDTELVETRPAGDRTFQKWAAVVVPSGEEQRYTCHVQHEGLPKPLTLRW (SEQ ID 097) B*57:72 SHSMRYFYTAMSRPGRGEPRFIAVGYVDDTQFVRFDSDAASPRMAPRAPWIEQEGP HLA12010 EYWDGETRNMKASAQTYRENLRIALRYYNQSEAGSHIIQVMYGCDVGPDGRLLRGH (181aa) DQSAYDGKDYIALNEDLSSWTAADTAAQITQRKWEAARVADQLRAYLEGLCVEWLR RYLENGKETLQRA (SEQ ID 098) B*57:73 SHSMRYFHTAMSRPGRGEPRFIAVGYVDDTQFVRFDSDAASPRMAPRAPWIEQEGP HLA12263 EYWDGETRNMKASAQTYRENLRIALRYYNQSEAGSHIIQVMYGCDVGPDGRLLRGH (181aa)DQSAYDGKDYIALNEDLSSWTAADTAAQITQRKWEAARVAEQLRAYLEGLCVEWLR RYLENGKETLQRA (SEQ ID 099) B*57:74 SHSMRYFYTAMSRPGRGEPRFIAVGYVDDTQFVRFDSDAASPRMAPRAPWIEQEGP HLA12294 EYWDGETRNMKASAQTYRENLRIALRYYNQSEAGSYIIQVMYGCDVGPDGRLLRGH (181aa) DQSAYDGKDYIALNEDLSSWTAADTAAQITQRKWEAARVAEQLRAYLEGLCVEWLR RYLENGKETLQRA (SEQ ID 100) B*57:75 SHSMRYFYTAMSRPGRGEPRFIAVGYVDDTQFVRFDSDAASPRMAPRATWIEQEGP HLA13002 EYWDGETRNMKASAQTYRENLRIALRYYNQSEAGSHIIQVMYGCDVGPDGRLLRGH (181aa) DQSAYDGKDYIALNEDLSSWTAADTAAQITQRKWEAARVAEQLRAYLEGLCVEWLR RYLENGKETLQRA (SEQ ID 101) B*57:76 SHSMRYFYTAMSRPGRGEPRFIAVGYVDDTQFVRFDSDAASPRMAPRAPWIEQEGP HLA13004 EYWDGETRNMKASAQTYRENLRIALRYYNQSEAGSHIIQVMYGCDVGPDGRLLRGH (181aa) DQFAYDGKDYIALNEDLSSWTAADTAAQITQRKWEAARVAEQLRAYLEGLCVEWLR RYLENGKETLQRA (SEQ ID 102) B*57:77 SHSMRYFYTAMSRPGRGEPRFIAVGYVDDTQFVRFDSDAASPRMAPRAPWIEQEGP HLA13480 EYWDGETRNMKASAQTYRENLRIALRYYNQSEAGSHIIQVMYGCDVGPDGLLLRGH (181aa) DQSAYDGKDYIALNEDLSSWTAADTAAQITQRKWEAARVAEQLRAYLEGLCVEWLR RYLENGKETLQRA (SEQ ID 103) Petition 870250111294, dated 04 / 12 / 2025, pp. 72 / 79 58 / 58 B*57:78 SHSMRYFYTAMSRPGRGEPRFIAVGYVDDTQFVRFDSDAASPRMAPWAPWIEQEGP HLA13379 EYWDGETRNMKASAQTYRENLRIALRYYNQSEAGSHIIQVMYGCDVGPDGRLLRGH (181aa) DQSAYDGKDYIALNEDLSSWTAADTAAQITQRKWEAARVAEQLRAYLEGLCVEWLR RYLENGKETLQRA (SEQ ID 104) B*57:79N MRVTAPRTVLLLLWGAVALTETWAGSHSMRYFYTAMSRPGRGEPRFIAVGYVDDTQ HLA13633 FVRFDSDAASPRMAPRAPWIEQEGPEYWDGETRNMKASAQTYRENLRIALRYYNQS (296aa) EAGSHIIQVMYGCDVGPDGRLLRGHDQSAYDGKDYIALNEDLSSWTAADTAAQITQ RKWEAARVAEQLRAYLEGLCVEWLRRYLENGKETLQRADPPKTHVTHHPISDHEAT LRCWALGFYPAEITLTWQRDGEDQTQDTELVETRPAGDRTFQKWAAVVVPSGEEQR YTCHVQHEGLPNPSPX (SEQ ID 105) B*57:80 SHSMRYFYTAMSRPGRGEPRFISVGYVDDTQFVRFDSDAASPRMAPRAPWIEQEGP HLA14154 EYWDGETRNMKASAQTYRENLRIALRYYNQSEAGSHIIQVMYGCDVGPDGRLLRGH (181aa) NQYAYDGKDYIALNEDLSSWTAADTAAQITQRKWEAARVAEQLRAYLEGLCVEWLR RYLENGKETLQRA (SEQ ID 106) B*57:81 SHSMRYFYTAMSRPGRGEPRFIAVGYVDDTQFVRFDSDAASPRMAPRAPWIEQEGP HLA14308 EYWEGETRNMKASAQTYRENLRIALRYYNQSEAGSHIIQVMYGCDVGPDGRLLRGH (181aa) DQSAYDGKDYIALNEDLSSWTAADTAAQITQRKWEAARVAEQLRAYLEGLCVEWLR RYLENGKETLQRA(362aa) B*57:82 EAGSHTLQRMYGCDVGPDGRLLRGHNQYAYDGKDYIALNEDLSSWTAADTAAQITQ RKWEAARVAEQLRAYLEGLCVEWLRRYLENGKETLQRADPPKTHVTHHPISDHEAT LRCWALGFYPAEITLTWQRDGEDQTQDTELVETRPAGDRTFQKWAAVVVPSGEEQR YTCHVQHEGLPKPLTLRWEPSSQSTVPIVGIVAGLAVLAVVVIGAVVAAVMCRRKS SGGKGGSYSQAACSDSAQGSDVSLTA (SEQ ID 108) Petition 870250111294, on 12 / 04 / 2025, page. 73 / 79

Claims

1 / 2 CLAIMS 1. Open HLA-B57 conformer characterized by comprising or consisting of a first and a second monomer, each monomer independently of the other monomer comprising a heavy chain of HLA-B57, and further comprising an Fc polypeptide sequence (crystallizable fragment) and optionally an amino acid linking the HLA-B57 chain and the Fc fragment, said HLA-B57 chain having an amino acid sequence selected from SEQ ID NOS: 1 to 108.

2. Open HLA-B57 conformer according to claim 1, characterized in that the first and / or second monomers additionally comprise a peptide epitope fragment.

3. Open HLA-B57 conformer according to claim 1 or 2, characterized in that the HLA-B57 chain consists only of the alpha HLA-B57 domains 1, 2 and 3.

4. Open HLA-B57 conformer according to any one of the preceding claims 1 to 3, characterized in that the HLA-B57 chain comprises the transmembrane domain and does not comprise the intracellular domain.

5. Open HLA-B57 conformer according to any one of claims 1 to 4, characterized in that the HLA-B57 chain corresponds to SEQ ID NO:

1.

6. HLA-B57 open conformer according to any one of claims 1 to 5, characterized by being for the treatment or prevention of cancer. Petition 870260043625, dated 08 / 05 / 2026, page 15 / 16 2 / 2 7. HLA-B57 open conformer according to any one of claims 1 to 5, characterized in that the Fc domain comprises constant regions of Ch2 and Ch3 heavy chains selected from any one of immunoglobulin type G (IgG), type A (IgA), type D (IgD), type E (IgE) or type M (IgM), and wherein said HLA-B57 open conformer is for the treatment or prevention of cancer.

8. Combination drug characterized by comprising a. an open HLA-B57 conformer, as defined in any one of claims 1 to 5, and b. a checkpoint inhibitor agent, particularly a checkpoint inhibitor antibody, and / or a checkpoint agonist agent, particularly a checkpoint agonist antibody.

9. Combination drug, according to claim 8, characterized in that a. said checkpoint inhibitor is selected from an inhibitor of the interaction of PD-1 with its ligand PD-L1 or PD-L2, particularly wherein the agent is selected from an antibody against either PD-1 or PD-L1, even more particularly wherein the agent is a monoclonal antibody against human PD-1 or PD-L1; or b. said checkpoint agonist is an antibody to potentiate immune responses by binding to 4-1BB, particularly a monoclonal antibody against 4-1BB. Petition 870260043625, dated 08 / 05 / 2026, p. 16 / 16

Images